Formulations and methods for treating dermatological disorders and diseases

ABSTRACT

The present invention provides compositions and methods for treating a dermatological disorder or disease.

CROSS-REFERENCE TO RELATED APPLICATION

The present application is a continuation of, and claims priority to,U.S. patent application Ser. No. 14/129,017, filed Feb. 26, 2014, nowissued as U.S. Pat. No. 9,968,540, which is the U.S. national phaseapplication filed under 35 U.S.C. § 371 claiming priority toInternational Patent Application No. PCT/US2012/043493, filed Jun. 21,2012, which claims priority pursuant to 35 U.S.C. § 119(e) to U.S.Provisional Application No. 61/500,909, filed Jun. 24, 2011, all ofwhich applications are hereby incorporated by reference herein in theirentireties.

BACKGROUND OF THE INVENTION

Skin is the soft outer covering of animals. In mammals, the skin is thelargest organ of the integumentary system and is made up of multiplelayers of ectodermal tissue. Because it interfaces with the environment,the skin has the important function of protecting the underlyingmuscles, bones, ligaments and internal organs from outside contact orinjury. The skin further plays a key role in protecting the body againstpathogens and excessive water loss. Among the skin's other functions arethermal insulation and regulation, gas absorption, sensation (the skincontains nerve endings that respond to heat and cold, touch, pressure,vibration, and tissue injury), and synthesis of vitamin D folates.

The skin may be affected by disorders or diseases that are diverse interms of cause, presentation and/or treatment. Among the most commonskin disorders or diseases are dermatitis/eczema, psoriasis and itching.

Dermatitis is generally caused by an allergic reaction to specificallergens. The term “dermatitis” is often used interchangeably with theterm “eczema,” which is also called dermatitis eczema or eczematousdermatitis. Dermatitis comprises conditions such as: contact dermatitis(caused by an allergen or an irritating substance); atopic dermatitis;dermatitis herpetiformis (which appears as a result of celiac disease);seborrheic dermatitis; nummular dermatitis (which tends to appear morefrequently in middle-aged people); stasis dermatitis (an inflammation onthe lower legs which is caused by buildups of blood and fluid and morelikely 24550027.2 to occur in people with varicose); and perioraldermatitis (which is similar to rosacea and often observed in womenbetween 20 and 60 years old).

Dermatitis symptoms range from skin rashes to bumpy rashes, includingblisters. Although every type of dermatitis has different symptoms,there are presentations that are common for all of them, includingredness of the skin, swelling, itching, skin lesions and sometimesoozing and scarring. Also, the area of the skin on which the symptomsappear may be different with each type of dermatitis. The symptoms ofcontact dermatitis usually appear at the site where the allergen gotinto contact with the skin. Although the symptoms of atopic dermatitisvary from person to person, the most common symptoms are dry, itchy, redskin. Typically affected skin areas include the folds of the arms, theback of the knees, wrists, face and hands. Less commonly there may becracks behind the ears, and various other rashes on any part of thebody. http://en.wikipedia.org/wiki/Dermatitis—cite_note-5 Itching is theprimary symptoms of this condition.

Treatment of dermatitis is made accordingly with the particular cause ofthe disease. Application of corticosteroidal creams or wet compressesand avoidance of allergens and irritants are part of most treatmentplans. For some types of dermatitis, non-steroidal medications andoccasional use of over-the-counter antihistamines may help relieve signsand symptoms.

Psoriasis is a chronic immune-mediated skin disease that appears whenthe immune system sends out faulty signals that speed up the growthcycle of skin cells. Psoriasis is not contagious and is commonly seen asred and white hues of scaly patches (plaques) appearing on the top firstlayer of the epidermis. Some patients, though, have no dermatologicalsymptoms. Plaques frequently occur on the skin of the elbows and knees,but can affect any area, including the scalp, palms of hands and solesof feet, and genitals. In contrast to eczema, psoriasis is more likelyto be found on the outer side of the joint.

Psoriasis is a chronic recurring condition that varies in severity fromminor localized patches to complete body coverage. Fingernails andtoenails are frequently affected (psoriatic nail dystrophy) and can beseen as an isolated symptom. Psoriasis can also cause inflammation ofthe joints, which is known as psoriatic arthritis. Between 10% and 40%of all people with psoriasis have psoriatic arthritis.

The cause of psoriasis is not fully understood, but it is believed tohave a genetic component and local psoriatic changes can be triggered byan injury to the skin. Various environmental factors have been suggestedas aggravating to psoriasis, including stress and withdrawal of systemiccorticosteroid. There are treatments available (such as topical agents,phototherapy, and systemic agents, such as methotrexate, cyclosporineand retinoids) but psoriasis treatment is challenging because of thechronic recurrent nature of the disease.

Itching is a sensation that causes the desire or reflex to scratch. Thebehavioral response patterns of pain and itching are intrinsicallydifferent: pain creates a withdrawal reflex, while itch leads to ascratch reflex. Unmyelinated nerve fibers for itch and pain bothoriginate in the skin; however, information for them is conveyedcentrally in two distinct systems that both use the same peripheralnerve bundle and spinothalamic tract. Itching may be triggered byinfections and infestations, environmental and allergic triggers,dermatological disorders (such as dry skin, psoriasis, eczema, sunburn,topical fungal infections (such as but not limited to athlete's foot,ringworm, and onychomycosis), hidradenitis suppurativa, scab healing,scar growth, development or emergence of moles, pimples and ingrownhairs from below the epidermis, punctate palmoplantar keratoderma anddandruff), medical disorders (malignancy or internal cancer such aslymphoma and Hodgkin's disease), jaundice and cholestasis, polycythemia,thyroid illness, hyperparathyroidism, uraemia, diabetes mellitus, irondeficiency anemia, menopause or changes in hormonal balances associatedwith aging), medication (morphine and other opiates, chloroquine) andconditions related to pregnancy (intrahepatic cholestasis of pregnancy,pruritic urticarial papules and plaques of pregnancy (PUPPP) andgestational pemphigoid).

Itching is often treated with over-the-counter and prescriptionanti-itch drugs, such as antihistamines (such as diphenhydramine),corticosteroids (such as hydrocortisone topical cream), counterirritants(such as mint oil, menthol, or camphor), and crotamiton. Phototherapy ishelpful for severe itching, especially if caused by renal failure.

Volatile anesthetics have been used safely for decades as generalanesthetics. Recently, volatile anesthetics have been shown to be usefulin the treatment of pain by administration routes rather thaninhalation. For example, International Application Publication No. WO2009/094460 discloses compositions and methods useful for reducing painin a subject in need thereof by delivering a volatile anesthetic in asolution or an emulsion to the subject. Besides producing analgesia,volatile anesthetics affect other receptors and have been shown to haveanti-inflammatory and muscle relaxing properties. For example,International Application Publication No. WO 2010/129686 disclosescompositions and methods useful for treating inflammation or a wound ina subject in need of such wound treatment or inflammation treatment bydelivering a volatile anesthetic to the wound or the inflammation site.Volatile anesthetics have been further shown to reduce cytokineproduction and release in both in vivo and in vitro inflammation model,and downregulate lipopolysaccharide (LPS)-induced production ofpro-inflammatory cytokines. Additionally, volatile anesthetics have beenshown to inhibit neutrophil function and decrease time to resolution ofinflammation. However, volatile anesthetics have not been so farsuccessfully used in the treatment of skin disorders or diseases.

There is a need in the art for improved formulations that may be used inthe treatment of dermatological disorders or diseases. There is also aneed in the art for improved methods for treating dermatologicaldisorders or diseases. The current invention fulfills these needs.

BRIEF SUMMARY OF THE INVENTION

The invention includes a pharmaceutically acceptable composition fortreating a dermatological disorder or disease. The composition comprisesa pharmaceutically acceptable excipient and at least one componentselected from the group consisting of: (a) a metered amount of avolatile anesthetic dissolved in a solution in an amount effective totreat the dermatological disorder or disease, wherein the solutionfurther comprises at least one extractive solvent in an amount effectiveto reduce volatility of the volatile anesthetic, wherein the solution isa component of an emulsion; (b) a metered amount of a liposomesuspension comprising a volatile anesthetic in an amount effective totreat the dermatological disorder or disease; (c) a metered amount of avolatile anesthetic dissolved in a solution in an amount effective totreat the dermatological disorder or disease, wherein the solutionfurther comprises at least one extractive solvent in an amount effectiveto reduce volatility of the volatile anesthetic, wherein the compositionfurther comprises a solubilizing agent; (d) a metered amount of amicro-droplet suspension, wherein the micro-droplet suspension comprisesa sphere of a volatile anesthetic in an amount effective to treat thedermatological disorder or disease, wherein the sphere is surrounded bya stabilizing layer of a phospholipid; and any combinations thereof.

In one embodiment, the at least one extractive solvent is selected fromthe group consisting of dimethyl sulfoxide (DMSO),N-methyl-2-pyrrolidone (NMP), dimethylformamide, dimethylacetamide,dimethylisosorbide, ethanol, propanol, PEG-400, PEG-300, diethyleneglycol monoethyl ether, isopropanol and any combinations thereof. Inanother embodiment, the composition is formulated for an administrationroute selected from the group consisting of topical, transdermal,mucosal, rectal, vaginal and any combinations thereof. In yet anotherembodiment, the volatile anesthetic is selected from the groupconsisting of isoflurane, halothane, enflurane, sevoflurane, desflurane,methoxyflurane, xenon and any mixtures thereof. In yet anotherembodiment, the dermatological disorder or disease is selected from thegroup consisting of eczema, dermatitis, psoriasis, itching, urticaria,allodynia, dry skin, sunburn, topical bacterial infections, topicalfungal infections, hidradenitis suppurativa, scab healing, scar growth,development or emergence of moles, pimples, ingrown hair, punctatepalmoplantar keratoderma, dandruff and any combinations thereof.

The invention also includes a method of treating a dermatologicaldisorder or disease in a subject in need thereof. The method comprisesadministering to the subject a pharmaceutically acceptable composition,wherein the composition comprises a pharmaceutically acceptableexcipient and at least one component selected from the group consistingof: (a) a metered amount of a volatile anesthetic dissolved in asolution in an amount effective to treat the dermatological disorder ordisease, wherein the solution further comprises at least one extractivesolvent in an amount effective to reduce volatility of the volatileanesthetic, wherein the solution is a component of an emulsion; (b) ametered amount of a liposome suspension comprising a volatile anestheticin an amount effective to treat the dermatological disorder or disease;(c) a metered amount of a volatile anesthetic dissolved in a solution inan amount effective to treat the dermatological disorder or disease,wherein the solution further comprises at least one extractive solventin an amount effective to reduce volatility of the volatile anesthetic,wherein the composition further comprises a solubilizing agent; (d) ametered amount of a micro-droplet suspension, wherein the micro-dropletsuspension comprises a sphere of a volatile anesthetic in an amounteffective to treat the dermatological disorder or disease, wherein thesphere is surrounded by a stabilizing layer of a phospholipid; and anycombinations thereof. In one embodiment, the at least one extractivesolvent is selected from the group consisting of dimethyl sulfoxide(DMSO), N-methyl-2-pyrrolidone (NMP), dimethylformamide,dimethylacetamide, dimethylisosorbide, ethanol, propanol, PEG-400,PEG-300, diethylene glycol monoethyl ether, isopropanol and anycombinations thereof. In another embodiment, the administering isperformed by a route selected from the group consisting of topical,transdermal, mucosal, rectal, vaginal and any combinations thereof. Inyet another embodiment, the volatile anesthetic is selected from thegroup consisting of isoflurane, halothane, enflurane, sevoflurane,desflurane, methoxyflurane, xenon and any mixtures thereof. In yetanother embodiment, the dermatological disorder or disease is selectedfrom the group consisting of eczema, dermatitis, psoriasis, itching,urticaria, allodynia, dry skin, sunburn, topical bacterial infections,topical fungal infections, hidradenitis suppurativa, scab healing, scargrowth, development or emergence of moles, pimples, ingrown hair,punctate palmoplantar keratoderma, dandruff and any combinationsthereof.

BRIEF DESCRIPTION OF THE DRAWINGS

For the purpose of illustrating the invention, there are depicted in thedrawings certain embodiments of the invention. However, the invention isnot limited to the precise arrangements and instrumentalities of theembodiments depicted in the drawings.

FIG. 1 illustrates a flowchart representing general methods for makingcompositions for the delivery of a formulated volatile anesthetic to theaffected area of a subject.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to the unexpected discovery that thecompositions and methods of the invention are useful to treat,ameliorate or prevent a dermatological disorder or disease, such as butnot limited to eczema, psoriasis and itching. In one embodiment, theitching is associated with pain. In another embodiment, the itching isnot associated with pain.

Definitions

As used herein, each of the following terms has the meaning associatedwith it in this section.

Unless defined otherwise, all technical and scientific terms used hereingenerally have the same meaning as commonly understood by one ofordinary skill in the art to which this invention belongs. Generally,the nomenclature used herein and the laboratory procedures in cellculture, molecular genetics, organic chemistry, and peptide chemistryare those well-known and commonly employed in the art.

The articles “a” and “an” are used herein to refer to one or to morethan one (i.e. to at least one) of the grammatical object of thearticle. By way of example, “an element” means one element or more thanone element.

As used herein, the term “about” will be understood by persons ofordinary skill in the art and will vary to some extent on the context inwhich it is used. As used herein when referring to a measurable valuesuch as an amount, a temporal duration, and the like, the term “about”is meant to encompass variations of ±20% or ±10%, more preferably ±5%,even more preferably ±1%, and still more preferably ±0.1% from thespecified value, as such variations are appropriate to perform thedisclosed methods.

The term “or,” as used herein, means “and/or” unless explicitlyindicated to refer to alternatives only or the alternatives are mutuallyexclusive, although the disclosure supports a definition that refers toonly alternatives and “and/or.”

The terms “inhibiting,” “reducing,” “preventing,” “diminishing,” andvariations of these terms, as used herein include any measurabledecrease, including complete or substantially complete inhibition.

The term “effective,” as that term is used in the specification and/orclaims, means adequate to accomplish a desired, expected, or intendedresult.

The phrase “extractive solvent,” as used herein, refers to a solventthat may interact with a volatile anesthetic in solution to reduce thevolatility of the volatile anesthetic without chemically reacting to thevolatile anesthetic, and/or enhances permeability of volatile anestheticinto the tissue of interest, favoring either achievement or enhancementof an intended pharmacological outcome. Extractive solvents alsocomprise compounds that do not necessarily extract, including vehiclesand functional components that may affect properties such as, but notlimited to, permeability or penetration.

As used herein, the term “enhanced permeability” refers to increase in(a) amount of volatile anesthetic delivered to the tissue of interestand/or (b) rate of delivery (i.e., rapid delivery) to the tissue ofinterest and/or (c) residence time of volatile anesthetic in the tissueof interest. Increase in residence time refers to a delay in eliminationof volatile anesthetic from tissue of interest.

As used herein, the words “comprising” (and any form of comprising, suchas “comprise” and “comprises”), “having” (and any form of having, suchas “have” and “has”), “including” (and any form of including, such as“includes” and “include”) or “containing” (and any form of containing,such as “contains” and “contain”) are inclusive or open-ended and do notexclude additional, unrecited elements or method steps.

As used herein, the term “dermatological disorder or disease” refers toa condition associated with the skin. Examples of these disorders ordiseases include, but are not limited to, eczema, dermatitis, psoriasis,itching, urticaria, dry skin, sunburn, topical bacterial infections(such as but not limited to impetigo, folliculitis, furunculosis,carbunculosis, ecthyma, erysipelas, cellulitis and necrotizingfasciitis), topical fungal infections (such as but not limited toathlete's foot, toe fungus, tinea corporis, tinea cruris, tinea faciei,tinea manuum, tinea pedis, any other form of ringworm, andonychomycosis), hidradenitis suppurativa, scab healing, scar growth,development or emergence of moles, pimples, ingrown hair, punctatepalmoplantar keratoderma and dandruff. Itching may be associated withone or more of these dermatological disorders or diseases, as well asallodynia, malignancy or internal cancer such as lymphoma and Hodgkin'sdisease, jaundice, cholestasis, polycythemia, thyroid illness,hyperparathyroidism, uraemia, diabetes mellitus, iron deficiency anemia,menopause or changes in hormonal balances associated with aging, use ofmorphine and other opiates, use of chloroquine, and conditions relatedto pregnancy (intrahepatic cholestasis of pregnancy, pruritic urticarialpapules and plaques of pregnancy (PUPPP) and gestational pemphigoid).

As used herein, the term “allodynia” refers to a form of pain due to astimulus which does not normally provoke pain. Allodynia may be eitherthermal or mechanical in origin, and often occurs after injury to asite. Allodynia is distinct from hyperalgesia, an extreme reaction to astimulus that is normally painful. There are different kinds or types ofallodynia: mechanical allodynia (also known as tactile allodynia), whichincludes atatic mechanical allodynia (pain in response to lighttouch/pressure) and dynamic mechanical allodynia (pain in response tobrushing); and thermal (hot or cold) allodynia (pain from normally mildskin temperatures in the affected area).

The term “topical,” as used herein, refers to the administration of thecompositions of the invention to the skin and underlying tissues, aswell as to administration to the mucosa and underlying tissues.

The term “treat” or “treatment,” as used herein, refers to thealleviation (i.e., “diminution”) and/or the elimination of asign/symptom or a source of a sign/symptom. By way of severalnon-limiting examples, a dermatological disorder or disease may betreated by alleviating or eliminating a sign/symptom of thedermatological disorder or disease. By way of a further example, adermatological disorder or disease may be treated by aiding (e.g.,accelerating) the healing process of the dermatological disorder ordisease.

As used herein, “additional ingredients” include, but are not limitedto, one or more of the following: excipients; surface active agents;dispersing agents; inert diluents; granulating and disintegratingagents; binding agents; lubricating agents; sweetening agents; flavoringagents; coloring agents; preservatives; physiologically degradablecompositions such as gelatin; aqueous vehicles and solvents; oilyvehicles and solvents; suspending agents; dispersing or wetting agents;emulsifying agents; demulcents; buffers; salts; thickening agents;fillers; emulsifying agents; antioxidants; antibiotics; antifungalagents; stabilizing agents; and pharmaceutically acceptable polymeric orhydrophobic materials. Other “additional ingredients” that may beincluded in the pharmaceutical compositions used in the practice of theinvention are known in the art and described, for example in Remington'sPharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton,Pa.), which is incorporated herein by reference.

DESCRIPTION

The invention includes a pharmaceutically acceptable compositioncomprising a metered amount of a volatile anesthetic dissolved in anaqueous solution in an amount effective to treat, ameliorate or preventa dermatological disorder or disease, wherein the solution furthercomprises at least one extractive solvent in an amount effective toreduce volatility of the volatile anesthetic, wherein the solution is acomponent of an emulsion, wherein the composition further comprises apharmaceutically acceptable excipient.

The invention further includes a pharmaceutically acceptable compositioncomprising a metered amount of a volatile anesthetic emulsion.

The invention also includes a pharmaceutically acceptable compositioncomprising a metered amount of a volatile anesthetic dissolved in asolution in an amount effective to treat, ameliorate or prevent adermatological disorder or disease, wherein the solution furthercomprises at least one extractive solvent in an amount effective toreduce volatility of the volatile anesthetic, wherein the compositionfurther comprises a solubilizing agent, wherein the composition furthercomprises a pharmaceutically acceptable excipient.

The invention further includes a pharmaceutically acceptable compositioncomprising a metered amount of a micro-droplet suspension, wherein themicro-droplet suspension comprises a sphere of a volatile anestheticsurrounded by a stabilizing layer of a phospholipid, wherein thecomposition further comprises a pharmaceutically acceptable excipient.

The invention also included a pharmaceutically acceptable compositioncomprising a metered amount of a volatile anesthetic dissolved in anaqueous solution in an amount effective treat, ameliorate or prevent adermatological disorder or disease, wherein the solution is a componentof an emulsion, wherein the composition further comprises apharmaceutically acceptable excipient.

In one embodiment, the at least one extractive solvent is selected fromthe group consisting of dimethyl sulfoxide (DMSO),N-methyl-2-pyrrolidone (NMP), dimethylformamide, dimethylacetamide,dimethylisosorbide, ethanol, propanol, PEG-400, PEG-300, diethyleneglycol monoethyl ether, isopropanol, and mixtures thereof. Preferably,the at least one extractive solvent comprises from about 0.1% to about75% of the solution.

In one embodiment, the solution is sterile. This may be achieved byensuring that all starting materials are sterile and maintaining themunder sterile conditions prior to administration. This may also beachieved by incorporation of an antimicrobial filter as has been donewith various types of infusions (see, for example, U.S. Pat. No.5,695,490).

In one embodiment, the composition is formulated for an administrationby a route selected from the group consisting of topical, transdermal,mucosal, rectal, and vaginal.

In one embodiment, the volatile anesthetic is selected from the groupconsisting of isoflurane, halothane, enflurane, sevoflurane, desflurane,methoxyflurane, xenon and mixtures thereof. In another embodiment, thevolatile anesthetic is isoflurane. Many of these agents are racemicmixtures. In some embodiments, the racemic mixtures are used. In otherembodiments, only the d-isomer or the 1-isomer of an agent is used (forexamples, see U.S. Pat. Nos. 5,114,715; 5,114,714 and 5,283,372). In yetanother embodiment, the solution may comprise from about 1% to about 99%v/v, from about 5% to about 70% v/v, or about 50% v/v, or about 25% v/v,or about 10% v/v volatile anesthetic in solution.

In one embodiment, the emulsion comprises a lipid. In anotherembodiment, the lipid comprises an agent selected from the groupconsisting of soybean oil, olive oil, peanut oil, castor oil, corn oiland sesame oil. The emulsion may further comprise an emulsifier.

In one embodiment, the volatile anesthetic is in the form of asuspension, a cream, a paste, an oil, a lotion, a gel, a foam, ahydrogel, an ointment, a liposome, an emulsion, a liquid crystalemulsion, or a nano-emulsion.

In one embodiment, the composition further comprises an antibiotic.

In one embodiment, the solution comprises at least one constituentselected from the group consisting of water and a saline solution.

In one embodiment, the diameter of the microdroplet ranges from about200 Angstroms up to about 10,000 Angstroms. In another embodiment, themicro-droplets are produced by sonication, homogenization,microfluidization or other processes involving high shear, wherein theratio of the volume of the volatile anesthetic to the weight of thephospholipid layer is at least 1.0 ml/g and the composition contains atleast 3% w/v of the volatile anesthetic. The invention further includesa method of treating, ameliorating or preventing a dermatologicaldisorder or disease in a subject in need thereof, wherein the methodcomprises administering to the subject a volatile anesthetic dissolvedin a solution in an amount effective to treat, ameliorate or prevent thedermatological disorder or disease, wherein the solution furthercomprises at least one extractive solvent in an amount effective toreduce volatility of the volatile anesthetic, wherein the solution is acomponent of an emulsion, wherein the route of administration isselected from the group consisting of topical, transdermal, mucosal,rectal, and vaginal.

The invention also includes a method of treating, ameliorating orpreventing a dermatological disorder or disease in a subject in needthereof, wherein the method comprises administering to the wound of thesubject a volatile anesthetic dissolved in a solution in an amounteffective to treat, ameliorate or prevent the dermatological disorder ordisease, wherein the solution further comprises at least one extractivesolvent in an amount effective to reduce volatility of the volatileanesthetic, wherein the composition further comprises a solubilizingagent, wherein the administration route is selected from the groupconsisting of topical, transdermal, mucosal, rectal, and vaginal.

The invention further includes a method of treating, ameliorating orpreventing a dermatological disorder or disease in a subject in needthereof, wherein the method comprises administering to the subject avolatile anesthetic dissolved in a solution in an amount effective totreat, ameliorate or prevent the dermatological disorder or disease,wherein the solution is a component of an emulsion, wherein theadministration route is selected from the group consisting of topical,transdermal, mucosal, rectal, and vaginal.

The invention also includes a method of treating, ameliorating orpreventing a dermatological disorder or disease in a subject in needthereof, wherein the method comprises administering to the subject aliposome suspension comprising a volatile anesthetic in an amounteffective to treat, ameliorate or prevent the dermatological disorder ordisease, wherein the administration route is selected from the groupconsisting of topical, transdermal, mucosal, rectal, and vaginal.

The invention further includes a method of treating, ameliorating orpreventing a dermatological disorder or disease in a subject in needthereof, the method comprising administering to the subject amicro-droplet suspension comprising a sphere of a volatile anestheticsurrounded by a stabilizing layer of a phospholipid in an amounteffective to treat, ameliorate or prevent the dermatological disorder ordisease, wherein the administration route is selected from the groupconsisting of topical, transdermal, mucosal, rectal, and vaginal.

In one embodiment, the dermatological disorder or disease is selectedfrom the group consisting of eczema, dermatitis, psoriasis, itching,urticaria, allodynia, dry skin, sunburn, topical bacterial infections(such as but not limited to impetigo, folliculitis, furunculosis,carbunculosis, ecthyma, erysipelas, cellulitis and necrotizingfasciitis), topical fungal infections (such as but not limited toathlete's foot, tinea faciei, any other form of ringworm, andonychomycosis), hidradenitis suppurativa, scab healing, scar growth,development or emergence of moles, pimples, ingrown hair, punctatepalmoplantar keratoderma and dandruff. In another embodiment, itchingmay be associated with a condition selected from the group consisting ofeczema, dermatitis, psoriasis, urticaria, dry skin, sunburn, topicalbacterial infections, topical fungal infections (such as but not limitedto athlete's foot, tinea faciei, any other form of ringworm, andonychomycosis), hidradenitis suppurativa, scab healing, scar growth,development or emergence of moles, pimples, ingrown hair, punctatepalmoplantar keratoderma, dandruff, malignancy or internal cancer suchas lymphoma and Hodgkin's disease, jaundice, cholestasis, polycythemia,thyroid illness, hyperparathyroidism, uraemia, diabetes mellitus, irondeficiency anemia, menopause or changes in hormonal balances associatedwith aging, use of morphine and other opiates, use of chloroquine, andconditions related to pregnancy (intrahepatic cholestasis of pregnancy,pruritic urticarial papules and plaques of pregnancy (PUPPP) andgestational pemphigoid).

In a non-limiting aspect, the presence of an extractive solvent in thecomposition of the invention comprising the volatile anesthetic mayprovide substantial advantages, including improving the physicalcharacteristics, pharmacological properties, and/or the ease of use ofthe composition. The extractive solvent may interact with the volatileanesthetic (in a non-limiting example, isoflurane) in a non-azeotropicfashion to effectively reduce vaporization or evaporation of thevolatile anesthetic. This effect of reducing volatility may be referredto as volatility attenuating effect (VAE). In this way, the shelf-life,durability, and/or ease of use of a volatile anesthetic composition maybe improved.

In a non-limiting aspect, the pharmacokinetics of the volatileanesthetic may be altered by the presence of an extractive solvent. Forexample, without wishing to be bound by any theory, the extractivesolvent may function in certain embodiments as a reservoir for thevolatile anesthetic such that the amount of volatile anesthetic retainedand/or the duration of retention is enhanced as compared to theapplication of pure non-formulated volatile anesthetic. Hence anextractive solvent renders delivery of the volatile anesthetic to aparticular site of action more effective. Similarly, in one embodimentwhere the volatile anesthetic composition contains an extractivesolvent, the extractive solvent may facilitate absorption, in terms ofrate and/or extent, of the volatile anesthetic into the site of action.Additionally, presence of an extractive solvent may have additive orsynergistic contributions to the volatility attenuation effect (VAE)rendered by the vehicle. In this aspect, the formulation may facilitateretention of the volatile anesthetic, which otherwise would be prone torapidly escape from the site of action due to its highly volatilenature, even at room temperature.

In a non-limiting aspect, when the formulation is a component of anemulsion or of a liposome, the emulsion or the liposome may function asa reservoir for the volatile anesthetic to retain the volatileanesthetic in a particular region more effectively and/or help deliverthe volatile anesthetic to site(s) of action. In yet anothernon-limiting aspect, the delivery of the volatile anesthetic may betailored as a sustained release. This may eliminate or reduce the needfor repeated dosing, and/or allow the achievement of the desiredsteady-state drug levels. Reduced volatility of the volatile anestheticin composition may also improve the ease of handling the volatileanesthetic compositions. This may facilitate manufacturing and packagingthe compositions of the invention. This may also avoid the possibilityof inhalation of the volatile anesthetic by the patient, health careprovider or packaging facility worker. Further, the reduced vaporizationof a volatile anesthetic in solution due to the presence of anextractive solvent may also reduce any potential concerns of a possiblerisk of fire and/or exposure at the medical facility.

In a non-limiting embodiment, when administered topically to an affectedarea, it is desirable to achieve a clinically effective concentration,which in some, but not necessarily all, cases may range, for example,from about 5 μg/mL to about 2,000,000 μg/mL of active agent in aformulation. In another non-limiting embodiment, in topicaladministration it is desirable to achieve a clinically effectiveconcentration, which in some, but not necessarily all, cases may range,for example, from about 2 μL to about 50 μL of solution per centimetersquare of area of application.

The invention further includes a sealed container comprising a volatileanesthetic solution of the present invention. The interior of thecontainer may be sterile. The container may be, for example, a syringe,a plastic bag, a collapsible plastic bag, a glass bottle, a glassampoule or a plastic bottle. The container may be itself a skin dressingor part of a skin dressing. In another aspect of present invention, acontainer that offers many advantages, such as, for example, ease ofapplication, unit dose configuration, and excellent container-closurecompatibility profile, is contemplated. This container may be such thatthe volatile anesthetic solution is contained in a crushable sealedampoule. The ampoule is in turn enclosed in protective covering on whichpressure is applied to crush the ampoule, which then releases volatileanesthetic solution for percolation through a flint-type tip whichcapped the ampoule in protective covering. When such packagingconfiguration is employed, care is taken to leave as little as possibleor ideally no headspace in ampoule for the volatile anesthetic to escapeand cause a change in solution composition over a period of shelf life.

Extractive Solvents

The volatile anesthetic compositions of the present invention maycontain a solvent, such as an extractive solvent, in combination with avolatile anesthetic. The phrase “extractive solvent,” as used herein,refers to a solvent that may interact with a volatile anesthetic in thecompositions of the invention to reduce the volatility of the volatileanesthetic without chemically reacting with the anesthetic. This phrasealso includes compounds that do not necessarily extract, includingvehicles and functional components, which may affect properties such as,but not limited to, permeability or penetration.

Certain extractive solvents interact in a non-azeotropic fashion with avolatile anesthetic. Nonetheless, the term “extractive solvent,” as usedherein, may include certain compounds, or mixtures thereof, whichinteract with a volatile anesthetic to form an azeotropic orpseudoazeotropic solution as long as the vapor pressure or evaporationof the volatile anesthetic from the solution is reduced. Extractivesolvents are also expected to attenuate volatility of volatileanesthetics such that the time required for a given amount of anestheticto escape from a given surface at a given temperature is increased,resulting in appreciable increase in time of contact of volatileanesthetic with the site of application before complete evaporation ofunabsorbed portion, as compared with the application of pure volatileanesthetic under similar conditions. In another embodiment, formulationsof current invention may contain an extractive solvent such that thisextractive solvent enhances permeability of volatile anesthetic into thetissue of interest thus favoring either achievement of or enhancement ofan intended pharmacological outcome. By way of example, but notlimitation, the tissue of interest described above may be skin or anyother tissue involved or believed to be involved, directly orindirectly, in the intended pharmacological outcome. Enhancedpermeability, as it applies to current invention, refers to increase in:(a) amount of volatile anesthetic delivered to the tissue of interest,and/or (b) rate of delivery (i.e., rapid delivery) to the tissue ofinterest, and/or (c) residence time of volatile anesthetic in the tissueof interest. Increase in residence time refers to a delay in eliminationof volatile anesthetic from tissue of interest.

As described below by chemical class as well as individual examples,various extractive solvents are envisioned for use with the presentinvention. The chemical classes contemplated in this invention comprisefatty alcohols, fatty acids, fatty amines, fatty acid esters, polyols,terpenes, esters, ethers, alkoxylated amides, poly propylene glycolethers, polyethylene glycols, poly propylene glycols and poly propyleneglycol ethers. Selected examples of individual ingredients contemplatedin current invention comprise of polyethylene glycol 400, polyethyleneglycol 300, diethylene glycol monoethyl ether, Labrasol, oleoylmacrogolglycerides (Labrafil M 1944), linoleoyl macrogolglycerides(Labrafil M2125), lauroyl macrogoglycerides (Labrafil M 2130), propyleneglycol dicaprylocaprate, propylene glycol monocaprylate (Capryol 90,Capryol PGMC), polypropylene glycol monolaurate (Lauroglycol 90,Lauroglycol FCC), polyglyceryl-3-dioleate, Peceol, isostearylisostearate, propylene glycol dipelargonate, polyglyceryl-3 dioleate,propylene glycol dipelargonate, octyldodecyl myristate, diethylsebacate, diisopropyl adipate, ethyl oleate, glyceryl isostearate,isopropyl isostearate, isopropyl myristate, isostearyl alcohol,isostearic acid, oleyl alcohol, eicosapentanenoic acid, docosahexaenoicacid, olive oil, peanut oil, soybean oil, castor oil, corn oil,cottonseed oil, peppermint oil, safflower oil, sesame oil, soybean oil,hydrogenated soybean oil, hydrogenated vegetable oil, medium chaintriglycerides coconut oil, palm oil, liquid lanolin, DMSO, NMP, and thelike.

The exact concentration of an extractive solvent may be determinedempirically and may vary according to the specific volatile anestheticused. In certain embodiments, the extractive solvent is present in thecomposition in an amount effective to reduce volatility of the volatileanesthetic in the composition. Particular care should also be taken toselect a concentration of an extractive solvent that results in littleor no toxicity when administered. It will be understood that, althoughcertain extractive solvents may exhibit properties which might be usedin various separation procedures (e.g., extractive distillation),extractive solvents according to embodiments of the present inventionare preferably included in pharmacological mixtures or solutionscomprising a volatile anesthetic in order to reduce the volatility of,rather than “extract,” the volatile anesthetic.

Including an extractive solvent in an anesthetic composition mayincrease the ease with which one may mix the solution prior toadministration. For example, in certain embodiments, mixing prior toadministration may be desirable if final formulation is selected to beself-emulsifying drug delivery system (SEDDS). In certain embodiments,sonication of the anesthetic solution prior to administration is notrequired when an extractive solvent is included in the volatileanesthetic composition. This advantage may be particularly useful ininstances (e.g., chronic administration) where the presence of asonicator could be noisy or distracting, such as an operating room, andthe elimination in the noise of a sonicator may also create an improvedenvironment for a conscious patient receiving a volatile anestheticcomposition, e.g., chronically or intermittently for pain relief.Eliminating the need for a sonicator, or other similar device, may alsobe particularly useful for reducing costs associated with administrationof a volatile anesthetic composition according to the present invention.The reduction in the bulk associated with the presence of a sonicatormay beneficially improve patient mobility. For example, in instanceswhere a patient may receive repeated administrations of an anestheticcomposition via a pump for analgesia, the reduced amount of equipmentmay improve mobility since the patient is not required to additionallymove a sonicator. In certain embodiments, sonication of the anestheticsolution prior to administration is required when an extractive solventis included in the volatile anesthetic composition.

Extractive solvents are known in the art and are typically used inextractive distillation for separating compounds with similar boilingpoints by retarding the vapor pressure of the principal component,thereby making possible an efficient separation which would not at alloccur in the absence of such solvent. For example, U.S. Pat. No.5,230,778 describes the purification of isoflurane by extractivedistillation using extractive solvents such as dimethylformamide. U.S.Pat. No. 5,336,429 describes solvents for cleaning electronic componentsand for degreasing metals comprising isoflurane and a lower alcohol oran ester, although these compositions are described as azeotropicmixtures with virtually constant boiling points. In contrast, thepresent invention provides pharmaceutical preparations, for example, forreating, ameliorating or preventing a dermatological disorder ordisease.

Certain extractive solvents known in the art, such as acetone asdescribed in U.S. Pat. No. 5,230,778, may be sufficiently toxic to limittheir inclusion in pharmaceutical preparations at higher concentrations.

In certain embodiments, an extractive solvent may interact as anazeotropic mixture with an anesthetic and reduce the volatility of theanesthetic. For example, ethanol may interact in an azeotropic fashionwith a volatile anesthetic as described in U.S. Pat. No. 5,230,778.

Various concentrations of an extractive solvent may be used with thepresent invention. For example, a composition of the present inventioncomprising a volatile anesthetic may comprise about 0.1%-99%, 0.1%-60%,5%-50%, 10%-40%, 5%-25%, 10%-30%, 10%-25%, 25%-50%, 10%-75%, 25%-75%,10%-65%, 25%-65%, 10%-60%, 25%-60%, 0.1%, 1%, 5%, 10%, 20%, 25%, 30%,35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, or any range derivabletherein, of an extractive solvent.

In certain embodiments, the extractive solvent is polyethylene glycol400 (PEG 400) or polyethylene glycol 300 (PEG 300). In otherembodiments, vehicle is olive oil or peanut oil or liquid lanolin ordiethylene glycol monoethyl ether.

In certain embodiments, the extractive solvent is diethylene glycolmonoethyl ether. In other embodiments, functional component is ethyloleate, glyceryl isostearate, isopropyl isostearate, isopropylmyristate, isostearyl alcohol, isostearic acid or oleyl alcohol. Incertain embodiments, the extractive solvent is dimethylsulfoxide (DMSO)or

N-methyl-2-pyrrolidone (NMP). In other embodiments, an extractivesolvent such as dimethylformamide, dimethylacetamide, ordimethylisosorbide may be used. In instances where acetone is used, careshould be taken to choose an appropriate dose in order to minimize anypossible toxicity.

Other extractive solvents include PEG-400, PEG-300, and diethyleneglycol monoethyl ether.

In various embodiments, it is envisioned that a medically acceptablealcohol, such as ethanol, propanol, or isopropanol may be used. In theseembodiments, the concentration of the alcohol used is sufficientlydilute in solution such that little or no irritation or neuron deathoccurs as a result of injection of the solution near a nerve.

A single extractive solvent, or multiple extractive solvents, may bepresent in an anesthetic composition of the present invention. Forexample, in certain embodiments, only a single extractive solvent (e.g.,DMSO, NMP or PEG 400) is present in a composition comprising a volatileanesthetic. In other embodiments, two, three, four or more extractivesolvents may be present in a composition comprising a volatileanesthetic. In certain embodiments, only a single volatile anesthetic(e.g., isoflurane) is present in an anesthetic composition of thepresent invention; in other embodiments, two, three, four or morevolatile anesthetics may be present in an anesthetic composition of thepresent invention. In certain embodiments, only a single extractivesolvent (e.g., diethylene glycol monoethyl ether) is present in ananesthetic composition of the present invention. In other embodiments,two, three, four or more extractive solvents may be present in ananesthetic composition of the present invention.

N-Methyl pyrrolidone:

N-methyl-2-pyrrolidone (NMP) is a solvent that may be included in thevolatile anesthetic compositions according to the present invention. NMPis a chemical compound with 5-membered lactam structure. It is a clearto slightly yellow liquid miscible with water and solvents includingethyl acetate, chloroform, benzene and lower alcohols or ketones. NMP isalso referred to by the chemical names 1-methyl-2-pyrrolidone orN-methyl-2-pyrrolidinone and m-pyrrole. NMP belongs to the class ofdipolar aprotic solvents, which also includes dimethylformamide,dimethylacetamide and dimethyl sulfoxide. Due to its good solvencyproperties, NMP has been used to dissolve a wide range of chemicals,particularly in the polymers field. It also used as a solvent forsurface treatment of textiles, resins and metal coated plastics or as apaint stripper.

NMP has been used in the medical industry to improve the solubility ofpoorly soluble drugs in certain pharmaceutical formulations. Forexample, NMP has been used with various drugs in veterinary medicine.Several patents have been issued, claiming improvements in drugsolubility by the use of NMP, as well as its applicability in topicaland transdermal pharmaceutical products for humans.

The relatively non-toxic properties of NMP make it particularly suitablefor use as a solvent with the present invention. NMP has a favorabletoxicity profile making it a suitable candidate for use in a variety oftopical, transdermal and parenteral dosage forms. NMP is available inGMP grade under the trademark Pharmasolve N-methyl-2-pyrrolidone sold byInternational Specialty Products (ISP; New Jersey, USA).

Dimethyl Sulfoxide (DMSO):

Dimethyl sulfoxide (DMSO) is used in certain embodiments of the presentinvention as a solvent. DMSO has the formula (CH₃)₂SO. DMSO is a polaraprotic solvent that dissolves both polar and non-polar compounds and ismiscible in a wide range of organic solvents as well as water.

DMSO is a relatively non-toxic compound, which makes it particularlysuitable for use as a solvent within the present invention. The relativelack of toxicity of DMSO is well established, and the potential use ofDMSO for medical purposes was established by Stanley Jacob at theUniversity of Oregon Medical School team, who discovered DMSO couldpenetrate the skin and other membranes without damaging them and couldcarry other compounds into a biological system. DMSO has also been usedas a cryoprotectant and as an anti-inflammatory agent. Dimethylsulfoxide dissolves a variety of organic substances, includingcarbohydrates, polymers, peptides, as well as many inorganic salts andgases.

In various embodiments, it is envisioned that lower concentrations, forexample, as low as from about 0.1% to about 10%, of DMSO in acomposition comprising a volatile anesthetic may be sufficient toeliminate the need for sonication of the composition prior toadministration. Higher concentrations, for example, from about 10% toabout 75% or higher, of DMSO in a composition comprising a volatileanesthetic may be sufficient to alter the pharmacokinetics of thevolatile anesthetic in such a way to allow for an increased rate and/orextent of volatile anesthetic delivered.

Volatile Anesthetics

In general, the halogenated ether anesthetics or volatile anestheticssuitable for use with the described compositions and methods includeagents which, although often liquid at room temperature, are capable ofeasily being becoming gaseous or are already gaseous at room temperatureand may treat dermatological disorders or diseases without significantside effects. It may be desirable, for example, to select a volatileanesthetic that is minimally metabolized by the body or is otherwiseinert. In this way, liver and kidney toxicity may be minimized.Similarly, it may be desirable for the volatile anesthetic to have ashort half-life, or be fast acting to promote titratability (i.e., thesubject may easily adjust the delivery amount for the dermatologicaldisorder or disease he or she is experiencing). An active agent gas thatdoes not produce tolerance (unlike opioids or local volatileanesthetics) or dependence (like opioids) may also be desirable.

Volatile anesthetics useful in the compositions and methods of theinvention include halogenated ether compounds, isoflurane, sevoflurane,halothane, enflurane, desflurane, methoxyflurane, and diethyl ethers. Incertain embodiments xenon may also be used with the present invention. Asingle agent or mixtures of agents may be particularly suitable for usewith the methods described herein.

In various embodiments, a gaseous volatile anesthetic may be used withthe present invention. For example, the gaseous volatile anesthetic maybe dissolved in a solution according to the present invention andadministered in a regional or local procedure, such as transdermally,topically, mucosally, rectally, orally, or vaginally. Importantly, thegaseous volatile anesthetic is not administrated by inhalation. Gaseousvolatile anesthetics other than halogenated anesthetics arecontemplated, and examples include xenon, nitrous oxide, cyclopropane,and ether, all of which may be used, in various embodiments, in racemicmixture form, or in d-isomer or 1-isomer forms. In various embodiments,other biologically active gases (for example, nitric oxide) may bedelivered in a solution to a subject according to the present invention.

More than one volatile anesthetic may be administered at one time, anddifferent volatile anesthetics may be administered at various timesthroughout a single treatment cycle. For example, two, three, four ormore volatile anesthetics may be simultaneously or repeatedlyadministered to a subject. When compounds are repeatedly administered toa subject, the duration between administration of compounds may be about1-60 seconds, 1-60 minutes, 1-24 hours, 1-7 days, 1-6 weeks or more, orany range derivable therein. In some instances, it may be desirable tostage the delivery of volatile anesthetics depending on their physicaland physiological properties. In certain clinical scenarios, a shorteracting agent may be desirable to treat acute dermatological disorders ordiseases, whereas a longer lasting agent may be more suited to chronicdermatological disorders or diseases.

Antibiotics

Antibiotics useful in the compositions and methods of the inventioninclude known antibiotics, as well as those yet to be discovered.Non-limiting examples include Amikacin, Aminoglycoside, Amoxicillin,Ampicillin, Azithromycin, Bacampicillin, Candicidin, Carbenicillin,Cefaclor, Cefadroxil, Cefamandole, Cefazolin, Cefdinir, Cefditoren,Cefepime, Cefonicid, Cefoperazone, Cefotaxime, Cefotetan, Cefoxitin,Cefpodoxime, Cefprozil, Ceftazidime, Ceftibuten, Ceftizoxime,Ceftriaxone, Cefuroxime, Cephalexin, Cephalosporins, Cephapirin,Cephradine, Ciprofloxacin, Clarithromycin, Clindamycin, Clotrimazole,Cloxacillin, Crysticillin, Cuprimyxin, Pentids, Permapen, Pfizerpen,Pfizerpen-AS, Wycillin, Demeclocycline, Dicloxacillin, Dirithromycin,Doxycycline, Enoxacin, Erythromycin, Flucloxacillin, Fluoroquinolone,Gatifloxacin, Gemifloxacin, Gentamicin, Haloprogin,Iodochlorohydroxyquin, Kanamycin, Ketolide, Levofloxacin, Lipopeptides,Lomefloxacin, Macrolides, Metronidazole, Mezlocillin, Minocycline,Moxifloxacin, Nafcillin, Neomycin, Netilmicin, Norfloxacin, Nystatin,Ofloxacin, Oxacillin, Oxytetracycline, Paromomycin, Penicillin G,Penicillin V, Penicillins, Piperacillin, Pivampicillin, Pivmecillinam,Roxithromycin, Sparfloxacin, Streptomycin, Sulfamethizole,Sulfamethoxazole, Sulfisoxazole, Sulfonamides, Telithromycin,Tetracyclines, Ticarcillin, Tobramycin, Tolnaftate,Trimethoprim-Sulfamethoxazole, Trovafloxacin, and Vancomycin.

Emulsions

As would be understood by one skilled in the art, an emulsion consistsof a mixture of two or more immiscible liquids (i.e., contains multiplephases) and emulsions are distinct from solutions, which contain one oressentially only one phase. One of the liquids (the dispersed phase) isdispersed in the other (the continuous phase). In one type of emulsion,a continuous liquid phase surrounds droplets of water (for example, awater-in-oil emulsion). In another type of emulsion, oil is dispersedwithin a continuous water phase (for example, an oil-in-water emulsion).Similarly, emulsification is the process by which emulsions areprepared.

In certain embodiments, a volatile anesthetic of the present inventionis a component of an emulsion, such as a water-in-oil or an oil-in-wateremulsion, including, but not limited to a lipid emulsion, such as asoybean oil emulsion. For example, a volatile anesthetic compositioncomprising a volatile anesthetic dissolved in a solution comprising anextractive solvent may also comprise a lipid emulsion or an oil-in-wateremulsion. In various embodiments, the emulsion of the invention maycontain an aqueous solution comprising a volatile anesthetic dissolvedin a solution, which may further comprise an extractive solvent.Inclusion of a water-in-oil or an oil-in-water emulsion, such as, forexample, a lipid emulsion, in an volatile anesthetic composition may beused, for example, to favorably affect the stability of the volatileanesthetic composition and/or alter the pharmacokinetics of theanesthetic. For example, lipid compositions, lipid emulsions,water-in-oil emulsions, and/or oil-in-water emulsions may be useful forthe transdermal, topical, mucosal, rectal, or vaginal delivery of thevolatile anesthetic compositions of the present invention. Certainemulsions of isoflurane have been prepared previously for intravenous(da Silva Telles et al., 2004, Rev. Bras. Anaestesiol Campianas54(5):2004) or epidural administration (Chai et al., 2008, British JAnesthesia 100:109-115; Chai et al., 2006, Anesthesiology 105:A743),both for inducing anesthesia.

In certain embodiments, the emulsion of the invention comprises avolatile anesthetic and water, and may further comprise an emulsifier.Emulsions of the invention also include, but are not limited to,nanoemulsions, which are emulsions with a mean droplet size less thanthose of emulsions. Nanoemulsions are sometimes referred to asmicroemulsions and submicroemulsions. Often, the physical appearance ofa nanoemulsion is transparent, rather than the often milky appearance ofan emulsion, due to the reduced mean droplet size. Emulsions of theinvention also include, but are not limited to, liquid crystalemulsions, such as those disclosed, for example, in U.S. PatentApplication Nos. 20070149624 and 20050238677, U.S. Pat. No. 5,183,585and International Patent Application No. WO 05108383.

In certain embodiments, the emulsion of the invention may have a lipidcomponent. In various embodiments, the lipid component may comprise anamount ranging from about 1% to 99%, from about 5% to about 75%, fromabout 10% to about 60%, from about 20% to about 50%, or from about 30%to about 40%, v/v of the emulsion. In various embodiments, the lipidcomponent of the emulsion may be soybean oil, long chain triglyceride,castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermintoil, safflower oil, sesame oil, soybean oil, hydrogenated soybean oil,hydrogenated vegetable oil, medium chain triglycerides coconut oil, palmsee oil and derivatives, medium chain (C8/C10) mono- and diglycerides,d-alpha-tocopherol, soy fatty acids, or combinations thereof. In certainembodiments, the lipid component of the emulsion is soybean oil.Commercially available lipid compositions that may be useful for theproduction of the volatile anesthetic compositions of the presentinvention include, but are not limited to, Intralipid®, Liposyn®, andNutrilipid®.

In other embodiments, the emulsion further comprises an emulsifier. Anemulsifier is a substance that stabilizes an emulsion. An emulsifier mayalso known as an emulgent. An emulsifier may also be a surfactant. Invarious embodiments, the emulsifier may be egg phospholipid, purifiedegg phospholipids, Polyoxyl 35 castor oil (Cremophor EL), Polyoxyl 40hydrogenated castor oil (Cremophor RH 40), Polyoxyl 60 hydrogenatedcastor oil (Cremophor RH 60), Polysorbate 20, Polysorbate 80,d-alpha-tocopheryl polyethylene glycol 1000 succinate, Solutol HS-15,propylene glycol, or combinations thereof. Various concentrations of anemulsifier may be used with the present invention. For example, acomposition of the present invention comprising a volatile anestheticmay comprise about 0.1%-99%, 0.1%-60%, 5%-50%, 10%-40%, 5%-25%, 10%-30%,10%-25%, 25%-50%, 10%-75%, 25%-75%, 10%-65%, 25%-65%, 10%-60%, 25%-60%,0.1%, 1%, 5%, 10%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%,70%, 75%, 80% or any range derivable therein, of an emulsifier.

In other embodiments, the emulsion of the invention has aperfluorocarbon component. In various embodiments, the perfluorocarboncomponent may comprise an amount ranging from about 0.1% to 99%, fromabout 5% to about 75%, from about 10% to about 60%, from about 20% toabout 50%, or from about 30% to about 40%, v/v of the emulsion. Invarious embodiments, perfluorocarbon may provide additional advantagesdue to its limited toxicity and ability to scavenge a large amount ofgas. In one embodiment, the emulsion of the invention comprises avolatile anesthetic, a perfluorocarbon, water and an emulsifier. Aperfluorocarbon, specifically perfluoro-n-octane, has been usedclinically, in cases of retinal detachment, by its instillation into theeye in place of the aqueous humor (see Chang, 1992, S. Intl. Ophthalmol.Clinic 32:153-163).

Liposomes and Micro-Droplets

In various embodiments, the volatile anesthetics of the presentinvention may be a component of a liposome suspension. A liposome (forexample, multilamellar, unilamellar, and/or multivesicular liposomes) isa microscopic, spherical, fluid-filled structure, with walls comprisingone or more layers of phospholipids and molecules similar in physicaland/or chemical properties to those that make up mammalian cellmembranes. By way of non-limiting examples, liposomes may be formed froma variety of natural membrane components, such as cholesterol,stearylamine, or phosphatidylcholine (see, for example, U.S. Pat. Nos.5,120,561 and 6,007,838, each of which is incorporated herein byreference in its entirety), or of pure surfactant components like DOPE(dioleoylphosphatidyl-ethanolamine). Liposomes may be formulated toincorporate a wide range of materials as a payload either in the aqueousor in the lipid compartments or in both. Generally, lipophilic activesubstances dissolve in the bilayer, amphiphilic substances becomeassociated with the phospholipid membrane and hydrophilic substancesoccur in solution in the enclosed aqueous volume (Artmann et al., 1990,Drug Res. 40 (II) 12:1363-1365; incorporated herein by reference in itsentirety).

Liposomes are useful as drug carriers or for topical use (Gehring etal., 1990, Drug Res. 40 (II) 12:1368-1371; incorporated herein byreference in its entirety). Liposomes have been used as carriers forlipophilic drugs like the anti-tumor and the anti-viral derivatives ofazidothymidine (AZT) (Kamps, et al., 1996, Biochim. Biophys. Acta.1278:183-190). Insulin has also been delivered via liposomes (Muramatsuet al., 1999, Drug Dev. Ind. Pharm. 25:1099-1105). For medical uses asdrug carriers, the liposomes may also be injected, and when they aremodified with lipids, their surfaces become more hydrophilic and hencetheir ability to persist may be increased. Polyethylene glycol-modifiedliposomes have been used as carriers for hydrophilic (water-soluble)anti-cancer drugs like doxorubicin. Liposomal derivatives ofmitoxantrone and others are especially effective in treating diseasesthat affect the phagocytes of the immune system because they tend toaccumulate in the phagocytes, which recognize them as foreign invaders(Rentsch et al., 1997, Br. J. Cancer 75:986-992). Liposomes have alsobeen used to carry normal genes into a cell to treat diseases caused bydefective genes (Guo et al., 2000, Biosci. Rep. 20:419-432). Theversatility of liposomes, due to the variable composition, enablesliposomes to be used to deliver vaccines, proteins, nucleotides,plasmids, drugs, cosmetics, or the volatile anesthetics of the inventionto the body.

Liposome compositions of the invention may comprise any range ofliposome and volatile anesthetic components, according to the methodsand detailed description set forth herein. By way of a non-limitingexample, a liposome component of a composition of the invention mayinclude from 0.1% to 99.9% liposome component, or more preferably, from0.1%-50% liposome component, and even more preferably, from 0.1%-30%liposome component. In various embodiments, the liposome of theinvention comprises cholesterol, stearylamine, phosphatidylcholine,dioleoylphosphatidylethanolamine, or combinations thereof.

In various embodiments, the volatile anesthetics of the presentinvention may also be a component of a microdroplet. A micro-droplet ofthe invention consists of a sphere of organic liquid phase drug thatranges in diameter from about 200 Angstroms to about 10,000 Angstromsthat is covered by a monolayer of a suitable lipid. Preferred lipids arephospholipids, which are natural constituents of biological membranesand as such are biologically compatible. Compounds useful for preparingmicrodroplets include phosphatidylcholine (lecithin), sphingomyelin,phosphatidic acid, phosphatidyl serine, phosphatidyl inositol,diphosphatidyl glycerol and phosphatidyl glycerol.

Micro-droplets may be prepared by sonication, including probe or bathsonication, homogenization, microfluidization or by high intensitymechanical agitation. The preferred method of preparing themicrodroplets of the invention is by sonication with a probe sonicator.Alternatively, micro-droplets may be prepared in a bath sonicator. Forsmall scale preparations a 1.0 cm diameter test tube is suspended, withuse of a test-tube clamp, in a bath sonicator filled with water. Thecomponents of the microdroplet are first grossly mixed by shaking,Vortex mixing, Polytron or other methods. The suspension is thenintroduced into the bath sonicator and sonicated for 1-2 hours. If thepreparation is to be done on a large scale, it is possible to omit thetest tube and introduce the components of the microdroplet directly intoa bath sonicator. Micro-droplets may also be produced by high intensitymechanical agitation. Useful methods include a Waring blender, aPolytron and high frequency shakers such as a commercial paint shaker.Other materials and methods useful in the preparation of microdropletsare known in the art and are described in U.S. Pat. Nos. 4,622,219,4,725,442, and 5,091,188, Haynes et al. (1989, J. Contr. Rel. 9:1-12)and Haynes et al. (1985, Anesthesiology 63:490-499), all of whichreferences are incorporated herein in their entirety.

Dosing

The amount of the volatile anesthetic to be administered depends on theparticular indication desired. For example, the dose will depend on thetype of dermatological disorder or disease intended to be treated. Thedose may be different, for instance, if the delivery of the volatileanesthetic is intended to reduce a chronic dermatological disorder ordisease as opposed to an acute dermatological disorder or disease. Thesubject's physical characteristics may also be important in determiningthe appropriate dosage. Characteristics such as weight, age, and thelike may be important factors. For example, the volatile anesthetic mayhave increased potency with age, as has been demonstrated in the case ofthe volatile anesthetic isoflurane.

The temperature of the volatile anesthetic may also be considered as afactor in selecting an appropriate dose, as the solubility of manyvolatile anesthetics may be affected by the temperature of the volatileanesthetic and/or solution. For example, increases in temperature mayincrease the solubility, and thus potency, of the volatile aestheticcomposition; this property has been demonstrated with certain volatileanesthetics. The particular dosage may also be dependent on the dosingregime chosen. For example, the volatile anesthetic composition may bedelivered continuously or periodically. Conversely, the volatileanesthetic composition may be administered as a single administration asa one-time event.

Volatile anesthetics (for example, halogenated volatile anestheticcompounds) may be applied in amounts leading to concentrations in therange of about 250 to about 50,000 nanograms/cm² of target site ofaction, depending on the volatile anesthetic selected and the desiredeffect. In certain embodiments, a halogenated volatile anesthetic orvolatile anesthetic may be administered to achieve a concentration offrom about 5 to about 5,000,000 nanograms/cm² of target site of action.While the dose range will vary depending on the compound selected andpatient variability, it is generally true that lower doses such as fromabout 0.01 to about 10,000 nanogram/cm² of target site of action aremore suitable for treating, ameliorating or preventing a moderatedermatological disorder or disease, while higher doses such as fromabout 10,000 nanogram/cm² of target site of action to about 500,000nanogram/cm² of target site of action or more are suitable for treatinga severe dermatological disorder or disease. Of course, the doses may begiven once (for example, for a minor single occurrence of dermatologicaldisorder or disease), repeatedly (for example, for a moderate or chronicdermatological disorder or disease), or continuously (for example, for asevere dermatological disorder or disease). Combinations of these dosingregimes may also be used. For example, a subject suffering from a severedermatological disorder or disease may require continuous dosing withperiodic additional dosing.

In embodiments where an volatile anesthetic (for example, a volatileanesthetic, isoflurane, etc.) is mixed in a solution, such as water,saline or an artificial CSF solution, the concentration of the volatileanesthetic may vary. For example, a solution may contain volatileanesthetic in a v/v ratio of from about 1 to about 99%, from about 10 toabout 75%, from about 10 to about 50%, from about 20 to about 50%, from30 to about 50%, from about 1 to about 45%, from about 1 to about 40%,from about 1 to about 35%, from about 1 to about 30%, from about 1 toabout 25%, from about 1 to about 20%, from about 1 to about 15%, fromabout 1 to about 10%, from about 1 to about 5%, from about 0.5 to about5%, from about 0.1 to about 5%, from about 0.1 to about 2.5%, from about0.5 to about 2.5%, or any range derivable therein. In these embodiments,the volatile anesthetic may be a volatile anesthetic, for example,isoflurane, and the solution may be water, a saline solution, artificialcerebrospinal fluid (ACSF), or other fluid.

The dosing and manner of delivery of the compositions of the inventionmay be adjusted to treat, ameliorate or prevent a dermatologicaldisorder or disease, for example, by varying the amount, concentration,frequency of administration, and timing of administration.

The volatile anesthetic solution may also contain one or more additives,such as a surfactant, PVP, a polymer, an antimicrobial agent, apreservative etc. In certain embodiments, an volatile anestheticcomposition of the present invention may comprise about: 0.1-90% of avolatile anesthetic such as isoflurane, methoxyflurane, or sevoflurane,0.1-99% of an extractive solvent such as NMP or DMSO, 0.1-99% saline,and 0-50% other additive(s) (for example, glycerol, a surfactant, PVP,etc.). In some embodiments, it may be desirable to produce aconcentrated formulation which may be subject to a final dilution priorto administration.

In various embodiments, a solution of about 10% volatile anesthetic,such as isoflurane, may be used; this solution may be administered as aone-time, continuously, and/or repeatedly to treat, ameliorate orprevent a dermatological disorder or disease. A further aspect of thecompositions and methods of the invention for the treatment of adermatological disorder or disease is the analgesic activity of thevolatile anesthetics. Thus, a 10% v/v solution of a volatile anestheticmay be used to treat, ameliorate or prevent a dermatological disorder ordisease. Higher concentrations and/or longer durations of volatileanesthetic may be used, in various embodiments, as necessary.

Methods of Active Agent Delivery

Volatile anesthetics of the present invention may be deliveredtopically. In some embodiments, specific concentrations of volatileanesthetics which may be used for topical delivery include from about100 to about 500,000 nanogram/cm² of target site of action, from about100 to about 250,000 nanogram/cm² of target site of action, from about100 to about 100,000 nanogram/cm² of target site of action, from about100 to about 50,000 nanogram/cm² of target site of action, from about100 to about 25,000 nanogram/cm² of target site of action, or from about100 to about 10,000 nanogram/cm² of target site of action. The specificconcentration of volatile anesthetic used may vary depending on thedesired effect, and in various embodiments the volatile anestheticcomposition is titrated for effect: thus the concentration of volatileanesthetic used or achieved in tissues may vary depending on thespecific desired result and/or the particular characteristics of thepatient such as sensitivity to the volatile anesthetic.

In some embodiments, specific concentrations of volatile anestheticswhich may be used to treat, ameliorate or prevent a dermatologicaldisorder or disease include from about 100 to about 500,000 nanogram/cm²of target site of action, from about 100 to about 250,000 nanogram/cm²of target site of action, from about 100 to about 100,000 nanogram/cm²of target site of action, from about 100 to about 50,000 nanogram/cm² oftarget site of action, from about 100 to about 25,000 nanogram/cm² oftarget site of action, or from about 100 to about 10,000 nanogram/cm² oftarget site of action.

The pharmaceutical compositions of the invention may be dispensed to thesubject under treatment with the help of an applicator. The applicatorto be used may depend on the specific medical condition being treated,amount and physical status of the pharmaceutical composition, and choiceof those skilled in the art.

The pharmaceutical compositions of the invention may be provided to thesubject or the medical professional in charge of dispensing thecomposition to the subject, along with instructional material. Theinstructional material includes a publication, a recording, a diagram,or any other medium of expression, which may be used to communicate theusefulness of the composition and/or compound used in the practice ofthe invention in a kit. The instructional material of the kit may, forexample, be affixed to a container that contains the compound and/orcomposition used in the practice of the invention or shipped togetherwith a container that contains the compound and/or composition.Alternatively, the instructional material may be shipped separately fromthe container with the intention that the recipient uses theinstructional material and the compound cooperatively. Delivery of theinstructional material may be, for example, by physical delivery of thepublication or other medium of expression communicating the usefulnessof the kit, or may alternatively be achieved by electronic transmission,for example by means of a computer, such as by electronic mail, ordownload from a website.

Other routes of administration to the affected area which arecontemplated include: transdermal, mucosal, rectal, and vaginal, ortopical (for example, in a carrier vehicle, a topical control releasepatch, in a wound dressing, a hydrocolloid, a foam, or a hydrogel, acream, a gel, a lotion, an ointment, a liquid crystal emulsion (LCE),and/or a micro-emulsion). An appropriate biological carrier orpharmaceutically acceptable excipient may be used. Compoundsadministered may, in various embodiments, be racemic, isomericallypurified, or isomerically pure.

Transmucosal Administration.

Transmucosal administration is carried out using any type of formulationor dosage unit suitable for application to mucosal tissue. For example,the selected active agent may be administered to the buccal mucosa in anadhesive tablet or patch, sublingually administered by placing a soliddosage form under the tongue, lingually administered by placing a soliddosage form on the tongue, administered nasally as droplets or a nasalspray, a non-aerosol liquid formulation, or a dry powder, placed withinor near the rectum (“transrectal” formulations), or administered to theurethra as a suppository, ointment, or the like.

Transrectal Administration.

Transrectal dosage forms may include rectal suppositories, creams,ointments, and liquid formulations (enemas). The suppository, cream,ointment or liquid formulation for transrectal delivery comprises atherapeutically effective amount of the selected active agent and one ormore conventional nontoxic carriers suitable for transrectal drugadministration. The transrectal dosage forms of the present inventionmay be manufactured using conventional processes. The transrectal dosageunit may be fabricated to disintegrate rapidly or over a period ofseveral hours. The time period for complete disintegration may be in therange of from about 10 minutes to about 6 hours, e.g., less than about 3hours.

Vaginal or Perivaginal Administration.

Vaginal or perivaginal dosage forms may include vaginal suppositories,creams, ointments, liquid formulations, pessaries, tampons, gels,pastes, foams or sprays. The suppository, cream, ointment, liquidformulation, pessary, tampon, gel, paste, foam or spray for vaginal orperivaginal delivery comprises a therapeutically effective amount of theselected active agent and one or more conventional nontoxic carrierssuitable for vaginal or perivaginal drug administration. The vaginal orperivaginal forms of the present invention may be manufactured usingconventional processes as disclosed in Remington: The Science andPractice of Pharmacy, supra (see also drug formulations as adapted inU.S. Pat. Nos. 6,515,198; 6,500,822; 6,417,186; 6,416,779; 6,376,500;6,355,641; 6,258,819; 6,172,062; and 6,086,909). The vaginal orperivaginal dosage unit may be fabricated to disintegrate rapidly orover a period of several hours. The time period for completedisintegration may be in the range of from about 10 minutes to about 6hours, e.g., less than about 3 hours.

Topical Formulations.

Topical formulations may be in any form suitable for application to thebody surface, and may comprise, for example, an ointment, cream, gel,lotion, solution, paste or the like, and/or may be prepared so as tocontain liposomes, micelles, and/or microspheres. In certainembodiments, topical formulations herein are ointments, creams and gels.

Transdermal Administration.

Transdermal compound administration, which is known to one skilled inthe art, involves the delivery of pharmaceutical compounds viapercutaneous passage of the compound into the systemic circulation ofthe patient. Topical administration may also involve the use oftransdermal administration such as transdermal patches or iontophoresisdevices. Other components may be incorporated into the transdermalpatches as well. For example, compositions and/or transdermal patchesmay be formulated with one or more preservatives or bacteriostaticagents including, but not limited to, methyl hydroxybenzoate, propylhydroxybenzoate, chlorocresol, benzalkonium chloride, and the like.Dosage forms for topical administration of the compounds andcompositions may include creams, sprays, lotions, gels, ointments, eyedrops, nose drops, ear drops, and the like. In such dosage forms, thecompositions of the invention may be mixed to form white, smooth,homogeneous, opaque cream or lotion with, for example, benzyl alcohol 1%or 2% (wt/wt) as a preservative, emulsifying wax, glycerin, isopropylpalmitate, lactic acid, purified water and sorbitol solution. Inaddition, the compositions may contain polyethylene glycol 400. They maybe mixed to form ointments with, for example, benzyl alcohol 2% (wt/wt)as preservative, white petrolatum, emulsifying wax, and tenox II(butylated hydroxyanisole, propyl gallate, citric acid, propyleneglycol). Woven pads or rolls of bandaging material, e.g., gauze, may beimpregnated with the compositions in solution, lotion, cream, ointmentor other such form may also be used for topical application. Thecompositions may also be applied topically using a transdermal system,such as one of an acrylic-based polymer adhesive with a resinouscrosslinking agent impregnated with the composition and laminated to animpermeable backing.

Examples of suitable skin contact adhesive materials include, but arenot limited to, polyethylenes, polysiloxanes, polyisobutylenes,polyacrylates, polyurethanes, and the like. Alternatively, thedrug-containing reservoir and skin contact adhesive are separate anddistinct layers, with the adhesive underlying the reservoir that, inthis case, may be either a polymeric matrix as described above, or be aliquid or hydrogel reservoir, or take some other form.

Additional Administration Forms.

Additional dosage forms of this invention include dosage forms asdescribed in U.S. Pat. Nos. 6,340,475; 6,488,962; 6,451,808; 5,972,389;5,582,837; and 5,007,790. Additional dosage forms of this invention alsoinclude dosage forms as described in U.S. Patent Application Nos.20030147952, 20030104062, 20030104053, 20030044466, 20030039688, and20020051820. Additional dosage forms of this invention also includedosage forms as described in PCT Application Nos. WO 03/35041, WO03/35040, WO 03/35029, WO 03/35177, WO 03/35039, WO 02/96404, WO02/32416, WO 01/97783, WO 01/56544, WO 01/32217, WO 98/55107, WO98/11879, WO 97/47285, WO 93/18755, and WO 90/11757.

Solutions After a halogenated ether volatile anesthetic has beenselected, it may be dissolved into a solution. The solution may be anaqueous-based solution, such as water, saline, or the like. In somevariations, other fluids and solutions may be appropriate.

Various formulations of saline are known in the art and may be used withthe present invention. For example, the saline may be lactated Ringer'ssolution, acetated Ringer's solution, phosphate buffered saline (PBS),Dulbecco's phosphate buffered saline (D-PBS), Tris-buffered saline(TBS), Hank's balanced salt solution (HBSS), or Standard saline citrate(SSC).

The saline solutions of the present invention are, in certainembodiments, “normal saline” (i.e., a solution of about 0.9% w/v ofNaCl). Normal saline has a slightly higher degree of osmolality comparedto blood; however, in various embodiments, the saline may be isotonic inthe body of a subject such as a human patient. In certain embodiments,“half-normal saline” (i.e., about 0.45% NaCl) or “quarter-normal saline”(i.e., about 0.22% NaCl) may be used with the present invention.Optionally, about 5% dextrose or about 4.5 g/dL of glucose may beincluded in the saline. In various embodiments, one or more salt,buffer, amino acid and/or antimicrobial agent may be included in thesaline.

In various embodiments, a preservative or stabilizer may be included inthe composition or solution. For example, the prevention of the actionof microorganisms may be brought about by preservatives such as variousantibacterial and antifungal agents, including but not limited toparabens (for example, methylparabens, propylparabens), chlorobutanol,phenol, sorbic acid, EDTA, metabisulfite, benzyl alcohol, thimerosal orcombinations thereof. Agents that may be included suitable for useinclude sterile aqueous solutions or dispersions and sterile powders forthe extemporaneous preparation of sterile solutions or dispersions (U.S.Pat. No. 5,466,468, specifically incorporated herein by reference in itsentirety). In all cases the composition is preferably sterile and mustbe fluid to facilitate easy injectability. Solutions are preferablystable under the conditions of manufacture and storage and must bepreserved against the contaminating action of microorganisms, such asbacteria and fungi. Examples of stabilizers which may be includedinclude buffers, amino acids such as glycine and lysine, carbohydratessuch as dextrose, mannose, galactose, fructose, lactose, sucrose,maltose, sorbitol, mannitol, and the like. Appropriate stabilizers orpreservatives may be selected according to the route of administrationdesired. A particle filter or microbe filter may be used, and may benecessary according to the route of administration desired.

The weight ranges of compounds in the solution may vary. For example, invarious embodiments, the composition may comprise about 1-5 wt %volatile anesthetic, about 1-5 wt % preservative/stabilizer, about 1-5wt % NaCl, and about 85%-97% water. The ratio of volatile anesthetic towater may be varied as needed to achieve the desired treatment ofdermatological disorders or diseases.

The solution and/or composition may also be sterilized prior toadministration. Methods for sterilization are well known in the art andinclude heating, boiling, pressurizing, filtering, exposure to asanitizing chemical (for example, chlorination followed bydechlorination or removal of chlorine from solution), aeration,autoclaving, and the like.

The active agent gas may be formulated into a solution in any number ofways. For example, it may be bubbled through the solution, for example,using a vaporizer, or it may be solubilized by agitation or bysonication. In certain embodiments, a volatile anesthetic such as ahalogenated ether or a volatile anesthetic may be measured in liquidform and directly admixed into a solution. Of course, other suitablemethods of dissolving the volatile anesthetic into solution may also beused. After the halogenated ether volatile anesthetic has beensolubilized, it may be administered to a subject in need of treatment ofa dermatological disorders or disease. In certain embodiments, avolatile anesthetic is admixed with a solution in a closed vacuumcontainer, and the combined solutions are then mechanically agitated for3-5 minutes and held in a thermo-neutral sonicator until use.

In certain embodiments, solutions of the present invention may be acomponent of an emulsion, such as a water-in-oil or an oil-in-wateremulsion, including a lipid emulsion, such as a soybean oil emulsion.Certain emulsions of isoflurane have been prepared previously forintravenous (da Silva Telles, et al., 2004, Rev. Bras. AnaestesiolCampianas 54(5):2004) or epidural administration (Chai et al. 2008,British J Anesthesia 100:109-115).

Pharmaceutical compositions of the present invention comprise aneffective amount of one or more volatile anesthetics or biologicallyactive gas or additional agent dissolved or dispersed in apharmaceutically acceptable carrier. The phrases “pharmaceutical orpharmacologically acceptable” refers to molecular entities andcompositions that do not produce an adverse, allergic or other untowardreaction when administered to an animal, such as, for example, a human,as appropriate. The preparation of a pharmaceutical composition thatcontains at least one volatile anesthetic or biologically active gas insolution or additional active ingredient will be known to those of skillin the art in light of the present disclosure, as exemplified by“Remington: The Science and Practice of Pharmacy,” 20th Edition (2000),which is incorporated herein by reference in its entirety. Moreover, foranimal (for example, human) administration, it will be understood thatpreparations should meet sterility, pyrogenicity, general safety andpurity standards as required by FDA Office of Biological Standards.

In various embodiments, the compositions of the present inventionfurther comprise cyclodextrin. Cyclodextrins are a general class ofmolecules composed of glucose units connected to form a series ofoligosaccaride rings (See Challa et al., 2005, AAPS PharmSciTech6:E329-E357). In nature, the enzymatic digestion of starch bycyclodextrin glycosyltransferase (CGTase) produces a mixture ofcyclodextrins comprised of 6, 7 and 8 anhydroglucose units in the ringstructure (α-, β-, and γ-cyclodextrin, respectively). Commercially,cyclodextrins are also produced from starch, but different, morespecific enzymes are used. Cyclodextrins have been employed informulations to facilitate the delivery of cisapride, chloramphenicol,dexamethasone, dextromethoraphan, diphenhydramine, hydrocortisone,itraconazole, and nitroglycerin (Welliver and McDonough, 2007, Sci WorldJ, 7:364-371). In various embodiments, the cyclodextrin of the inventionis hydroxypropyl-Beta-cyclodextrin, sulfobutylether-beta-cyclodextrin,alpha-dextrin or combinations thereof. In certain embodiments,cyclodextrin may be used as a solubilizing agent.

In various other embodiments, compositions of the present invention maycomprise human serum albumin purified from plasma, or recombinant humanserum albumin. In certain embodiments, human serum albumin may be usedas a solubilizing agent. In other embodiments, the compositions of theinvention may comprise propylene glycol. In other embodiments, thecompositions of the invention may comprise perfluorooctyl bromide. Inother embodiments, the compositions of the invention may compriseperfluorocarbon. In certain embodiments, perfluorocarbon may be used asa solubilizing agent.

In various embodiments, a preservative or stabilizer may be included inthe composition or solution. For example, the prevention of the actionof microorganisms may be brought about by preservatives such as variousantibacterial and antifungal agents, including but not limited toparabens (for example, methylparabens, propylparabens), chlorobutanol,phenol, sorbic acid, EDTA, metabisulfite, benzyl alcohol, thimerosal orcombinations thereof. Agents which may be included suitable for useinclude sterile aqueous solutions or dispersions and sterile powders forthe extemporaneous preparation of sterile solutions or dispersions (U.S.Pat. No. 5,466,468, specifically incorporated herein by reference in itsentirety). In all cases the composition is preferably sterile and mustbe fluid to facilitate easy injectability. Solutions are preferablystable under the conditions of manufacture and storage and must bepreserved against the contaminating action of microorganisms, such asbacteria and fungi. Examples of stabilizers which may be includedinclude buffers, amino acids such as glycine and lysine, carbohydratessuch as dextrose, mannose, galactose, fructose, lactose, sucrose,maltose, sorbitol, mannitol, etc. Appropriate stabilizers orpreservatives may be selected according to the route of administrationdesired. A particle filter or microbe filter may be used and may benecessary according to the route of administration desired.

Pharmaceutical Compositions and Therapies

Administration of compositions of the invention in a method of treatmentmay be achieved in a number of different ways, using methods known inthe art. Such methods include, but are not limited to, topicallyadministering solutions, suspensions, creams, pastes, oils, lotions,gels, foam, hydrogel, ointment, liposomes, emulsions, liquid crystalemulsions, and nanoemulsions.

The therapeutic and prophylactic methods of the invention thus encompassthe use of pharmaceutical compositions of the invention. Theformulations of the pharmaceutical compositions described herein may beprepared by any method known or hereafter developed in the art ofpharmacology. In general, such preparatory methods include the step ofbringing the active ingredient into association with a carrier or one ormore other accessory ingredients, and then, if necessary or desirable,shaping or packaging the product into a desired single- or multi-doseunit. For example unit dose container may be such that volatileanesthetic solution is contained in a crushable sealed ampoule which inturn is enclosed in protective covering on which pressure is applied tocrush the ampoule which then releases volatile anesthetic solution forpercolation through a flint-type tip which capped the ampoule inprotective covering. When such packaging configuration is employed, careis taken to leave as little as possible or ideally no headspace inampoule for the volatile anesthetic to escape and cause a change insolution composition over a period of shelf life.

Although the description of pharmaceutical compositions provided hereinare principally directed to pharmaceutical compositions which aresuitable for ethical administration to humans, it will be understood bythe skilled artisan that such compositions are generally suitable foradministration to animals of all sorts, including mammals. Modificationof pharmaceutical compositions suitable for administration to humans inorder to render the compositions suitable for administration to variousanimals is well understood, and the ordinarily skilled veterinarypharmacologist may design and perform such modification with merelyordinary, if any, experimentation. Subjects to which administration ofthe pharmaceutical compositions of the invention is contemplatedinclude, but are not limited to, humans and other primates, mammalsincluding commercially relevant mammals such as non-human primates,cattle, pigs, horses, sheep, cats, and dogs.

Pharmaceutical compositions that are useful in the methods of theinvention may be prepared, packaged, or sold in formulations suitablefor ophthalmic, vaginal, topical, intranasal, buccal, or another routeof administration.

A pharmaceutical composition of the invention may be prepared, packaged,or sold in bulk, as a single unit dose, or as a plurality of single unitdoses. A unit dose is discrete amount of the pharmaceutical compositioncomprising a predetermined amount of the active ingredient. The amountof the active ingredient is generally equal to the dosage of the activeingredient which would be administered to a subject or a convenientfraction of such a dosage such as, for example, one-half or one-third ofsuch a dosage.

The relative amounts of the active ingredient, the pharmaceuticallyacceptable carrier, and any additional ingredients in a pharmaceuticalcomposition of the invention will vary, depending upon the identity,size, and condition of the subject treated and further depending uponthe route by which the composition is to be administered. By way ofexample, the composition may comprise between 0.1% and 100% (w/w) activeingredient.

In addition to the active ingredient, a pharmaceutical composition ofthe invention may further comprise one or more additionalpharmaceutically active agents. One non-limiting example of such anadditional pharmaceutically active agent is an antimicrobial agent, suchas an antibiotic.

Controlled- or sustained-release formulations of a pharmaceuticalcomposition of the invention may be made using conventional technology.

Formulations of a pharmaceutical composition suitable for topicaladministration comprise the active ingredient combined with apharmaceutically acceptable carrier, such as sterile water or sterileisotonic saline. Formulations may be prepared, packaged, or sold in unitdosage form, such as in ampules, crushable or otherwise, or inmulti-dose containers containing a preservative. Formulations fortopical administration include, but are not limited to, suspensions,solutions, emulsions in oily or aqueous vehicles, solutions,suspensions, creams, pastes, oils, lotions, gels, foam, hydrogel,ointment, liposomes, emulsions, liquid crystal emulsions, nanoemulsions,implantable sustained-release or biodegradable formulations. Suchformulations may further comprise one or more additional ingredientsincluding, but not limited to, suspending, stabilizing, or dispersingagents.

The pharmaceutical compositions may be prepared, packaged, or sold inthe form of a sterile aqueous or oily suspension or solution. Thissuspension or solution may be formulated according to the known art, andmay comprise, in addition to the active ingredient, additionalingredients such as the dispersing agents, wetting agents, or suspendingagents described herein. Such sterile formulations may be prepared usinga non-toxic acceptable diluent or solvent, such as water or 1,3-butanediol, for example. Other acceptable diluents and solvents include, butare not limited to, Ringer's solution, isotonic sodium chloridesolution, and fixed oils such as synthetic mono- or di-glycerides. Otherformulations that are useful include those which comprise the activeingredient in a liposomal preparation, or as a component of abiodegradable polymer system. Compositions for sustained release orimplantation may comprise pharmaceutically acceptable polymeric orhydrophobic materials such as an emulsion, an ion exchange resin, asparingly soluble polymer, or a sparingly soluble salt.

In some embodiments, the pharmaceutical compositions of the inventionmay be contained in a crushable ampule irrespective of the route ofdelivery to the patient. Throughout this disclosure, various aspects ofthis invention may be presented in a range format. It should beunderstood that the description in range format is merely forconvenience and brevity and should not be construed as an inflexiblelimitation on the scope of the invention. Accordingly, the descriptionof a range should be considered to have specifically disclosed all thepossible sub-ranges as well as individual numerical values within thatrange. For example, description of a range such as from 1 to 6 should beconsidered to have specifically disclosed sub-ranges such as from 1 to3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc.,as well as individual and partial numbers within that range, forexample, 1, 2, 3, 4, 5, 5.5 and 6. This applies regardless of thebreadth of the range.

It is contemplated that any embodiment discussed in this specificationmay be implemented with respect to any method or composition of theinvention, and vice versa. Furthermore, compositions of the inventionmay be used to achieve methods of the invention.

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, numerous equivalents to thespecific procedures, embodiments, claims, and examples described herein.Such equivalents were considered to be within the scope of thisinvention and covered by the claims appended hereto. For example, itshould be understood, that modifications in reaction conditions,including but not limited to reaction times, reaction size/volume, andexperimental reagents, such as solvents, catalysts, pressures,atmospheric conditions, e.g., nitrogen atmosphere, andreducing/oxidizing agents, with art-recognized alternatives and using nomore than routine experimentation, are within the scope of the presentapplication.

It is to be understood that wherever values and ranges are providedherein, all values and ranges encompassed by these values and ranges,are meant to be encompassed within the scope of the present invention.Moreover, all values that fall within these ranges, as well as the upperor lower limits of a range of values, are also contemplated by thepresent application.

The following examples further illustrate aspects of the presentinvention. However, they are in no way a limitation of the teachings ordisclosure of the present invention as set forth herein.

EXPERIMENTAL EXAMPLES

The invention is now described with reference to the following Examples.These Examples are provided for the purpose of illustration only, andthe invention is not limited to these Examples, but rather encompassesall variations that are evident as a result of the teachings providedherein.

Example 1

Preparation of Isoflurane Dissolved in Saline

Isoflurane was dissolved into saline using the following method (alsoreferred to as the “bubbling” method). A mock vaporizing device wascreated using a 500 ml modified Erlenmeyer flask (2 inlets and 1catheter into the liquid phase). The flask was partially filled with0.9% normal saline and a stoppered glass pipette was inserted into thebottom of the liquid phase for injection of isoflurane. A second egresspipette allowed egress of gas from the closed container. 2% isofluranesolution in oxygen at 2 L/min was injected through the pipette,saturating the 0.9% saline solution after approximately 10 minutes ofbubbling.

Example 2

Isoflurane Dissolved in Artificial Cerebrospinal Fluid

Isoflurane dissolved in ACSF was prepared by the following method.Isoflurane was mixed in a closed vacuum container in a v/v ratio of10-50% with buffered salt solution that approximates cerebrospinal fluid(pH 7.4) with the following composition (in mM): NaCl, 120; KCl, 3;NaHCO₃, 25; CaCl₂, 2.5; MgCl₂, 0.5; glucose, 12. The combined solutionswere mechanically agitated for 3-5 minutes and then held in athermo-neutral sonicator until use.

Example 3

Preparation of Anesthetic Compositions Comprising an Extractive Solvent

The following solutions were prepared. Isoflurane was obtained. NMP wasobtained from Sigma-Aldrich Chemical company. A 40% (v/v) isoflurane-NMPsolution was made adding 40 ml of isoflurane to 60 ml of NMP. A 40%(v/v) isoflurane-ethanol solution was made adding 40 ml of isoflurane to60 ml of ethanol.

Saline compositions with varying concentrations of isoflurane and NMPwere made by mixing the above NMP-isoflurane solution with saline asfollows:

Base-Isoflurane Saline Compositions % % Sample (ml) (ml) Isoflurane NMPA 0 10 40% 60% B 2 8 32 48 C 4 6 24 36 D 5 5 20 30 E 6 4 16 24 F 8 2 812 G 10 0 0 0

Control compositions with varying concentrations of isoflurane-ethanolwere made by mixing the above isoflurane-ethanol compositions withsaline as follows:

Control-Isoflurane Saline Compositions % % Sample (ml) (ml) IsofluraneEthanol H 0 10 40% 60% I 2 8 32 48 J 4 6 24 36 K 5 5 20 30 L 6 4 16 24 N8 2 8 12 M 10 0 0 0

To determine the stability of the compositions, the following experimentmay be performed. Each sample is divided into two containers containing5 mls of the sample. One of the samples is capped. The other sample isleft uncapped. Over time (1 hour, 6 hour, 24 hour, etc.), the samplesare examined to see if the isoflurane has separated from solution.Furthermore, the concentration of isoflurane in each solution may bedetermined at each time point. The uncapped sample may be compared tothe capped sample to determine the stability of the solution.Furthermore, the isoflurane-NMP compositions may then be compared to thecontrol compositions. It is anticipated that the anesthetic compositionswill remain miscible at all concentrations.

Example 4

Preparation of Anesthetic Compositions Comprising an Emulsion

Solutions of emulsified isoflurane are prepared at room temperature (20°C.) by adding liquid isoflurane to 30% Intralipid® (Sigma-Aldrich) ingas-tight glass bottles fitted with Teflon stoppers. The bottles arethen vibrated on a vibrator at 50 Hz for 30 minutes. (For examples see,Zhou et al, 2006, Anesth Analg 102:129-34; Taheri et al., 1991, AnesthAnalg 1991; 72:627-34).

30% Intralipid Isoflurane % Sample (ml) (ml) Isoflurane A 40 1.28 3.1 B40 2.55 6.0 C 40 3.48 8.0 D 40 4.45 10.0 E 40 10.0 20.0 F 40 26.67 40.0

To determine the stability of the compositions, the following experimentis performed. Each sample is divided into two containers containing 5 mlof the sample. One of the samples is capped. The other sample is leftuncapped. Over time (1 hour, 6 hour, 24 hour, etc.), the samples areexamined to see whether the isoflurane has separated from solution, orwhether the lipid phase has separated from the aqueous phase.Furthermore, the concentration of isoflurane in each solution may bedetermined at each time point. The uncapped sample may be compared tothe capped sample to determine the stability of the solution. It isanticipated that the anesthetic compositions will not separate at allconcentrations.

One of skill in the art will realize that emulsions of isoflurane may bemade using other lipids, including other emulsion preparations, such as10% (w/v) Intralipid® or 20% (w/v) Intralipid®, using variations of themethods described herein. Other commercially available lipidcompositions that may be useful for the production of the volatileanesthetic compositions of the present invention include, but are notlimited to, Liposyn® (B. Braun) and Nutrilipid® (B. Braun).

One of skill in the art will also realize that emulsions of desflurane,sevoflurane, isoflurane, enflurane, methoxyflurane and halothane may beproduced using variations of the methods described herein.

Example 5

Preparation of Anesthetic Compositions Comprising an Extractive Solventand an Emulsion

The following solutions and emulsions are prepared. Isoflurane isobtained. NMP is obtained from Sigma-Aldrich Chemical company. A 40%(v/v) isoflurane-NMP solution is made by adding 40 ml of isoflurane to60 ml of NMP (as in Example 4).

Emulsion compositions with varying concentrations of isoflurane and NMPare prepared by mixing the above NMP-isoflurane solution with 30%Intralipid (Sigma-Aldrich) at room temperature (20° C.) in gas-tightbottles fitted with Teflon stoppers as follows:

40% (v/v) 30% Intralipid isoflurane-NMP % % Sample (ml) (ml) IsofluraneNMP A 40 3.37 3.1 4.7 B 40 7.06 6.0 9.0 C 40 10.0 8.0 12.0 D 40 13.3410.0 15.0 E 40 40.0 20.0 30.0

After mixing, the bottles are vibrated on a vibrator at 50 Hz for 30minutes. To determine the stability of the compositions, the followingexperiment is performed. Each sample is divided into two containerscontaining 5 ml of the sample. One of the samples is capped. The othersample is left uncapped. Over time (1 hour, 6 hour, 24 hour, etc.), thesamples are examined to see whether the isoflurane has separated fromsolution, or whether the lipid phase has separated from the aqueousphase. Furthermore, the concentration of isoflurane in each solution isdetermined at each time point. The uncapped sample may be compared tothe capped sample to determine the stability of the solution. It isanticipated that the anesthetic compositions will not separate at allconcentrations.

One of skill in the art will realize that emulsions of isoflurane may bemade using other lipids, including other emulsion preparations, such as10% (w/v) Intralipid® or 20% (w/v) Intralipid®, using variations of themethods described herein. Other commercially available lipidcompositions that may be useful for the production of the volatileanesthetic compositions of the present invention include, but are notlimited to, Liposyn® (B. Braun) and Nutrilipid® (B. Braun).

One of skill in the art will also realize that emulsions of desflurane,sevoflurane, isoflurane, enflurane, methoxyflurane and halothane may beproduced using variations of the methods described herein.

Example 6

Stability of Isoflurane Formulations

In the Examples that follow, the stability of isoflurane in thedescribed compositions was determined in two ways. First, thecompositions were examined for the presence of phase separation at themacroscopic level. Secondly, isoflurane content of the compositions wasdetermined by weighing the remaining isoflurane in the composition whenthey were left uncapped over time. Briefly, glass vials were filled with5-10 ml of the composition vehicle and then weighed; one of themreceived only vehicle (i.e., no isoflurane) and served as control. Theother vials received varying amounts of isoflurane. They were leftuncapped in the hood. Over time, the vials were weighed to see if theisoflurane stayed in the composition or had evaporated. The amountevaporated over time in the vehicle control was subtracted from that inthe isoflurane-containing composition.

The pure form of isoflurane is a volatile anesthetic. In order to assessthe volatility of isoflurane, two vials received the indicated amountsof pure form isoflurane. The vials were placed in the chemical fume hoodand left uncapped. The vials were weighed at the indicated times todetermine the amount of evaporated isoflurane. As it is shown in thetable below 0.7893 g isoflurane was evaporated within 3 hours, while3.4825 g isoflurane took approximately 8 hrs to evaporate completely.These amounts of isoflurane are similar to the amounts of isofluranethat were used to prepare the isoflurane compositions in the Examplesthat follow.

Pure form 0 h 0.25 h 1 h 2 h 3 h 5 h of (% (% (% (% (% (% isofluraneremaining remaining remaining remaining remaining remaining (g) iso)iso) iso) iso) iso) iso) 7 h 8 h 0.7893 100 85 52 14 0 3.4825 100 96 8675 62 38 13 3

Example 7

Preparation of Isoflurane Solution (v/v) with NMP

Pure isoflurane USP (Forane) liquid was mixed with NMP (Sigma-Aldrich)in the indicated concentrations; the mixture was vortexed vigorously toprepare homogenous isoflurane-NMP solution. In order to reduce theamount of NMP in the solution, saline (0.9% NaCl) was added to themixture.

NMP Saline Isoflurane Appearance of (%) (%) (%) solutions 1 90 — 10Clear 2 60 — 40 Clear 3 63 27 10 Clear 4 72 20 8 Clear

Isoflurane 0 h 0.25 h 1 h 16 h 24 h concentration (% remaining (%remaining (% remaining (% remaining (% remaining in NMP iso) iso) iso)iso) iso) 10 100 99 99 94 91 30 100 99 98 90 86

As it is shown in the tables above, 10% and 40% of isoflurane was mixedwith NMP, and the resulting solution looked clear. Moreover, theaddition of NMP reduced the volatility of isoflurane, as compared withExample 6.

Example 8

Preparation of Emulsified Isoflurane (v/v) in Intralipid

Pure isoflurane USP (Forane) liquid is mixed with Intralipid 20% or 30%(Baxter) at the indicated concentrations; the mixture was vortexedvigorously and sonicated for 30 minutes to prepare homogenousisoflurane-intralipid emulsion.

Lipid Isoflurane Appearance of Emulsion Concentration Emulsions 1 20%Intralipid  1-6% Homogenous 2 30% intralipid 6-10% Homogenous

Isoflurane 0 h 0.25 h 1 h 16 h 24 h concentration in (% remaining (%remaining (% remaining (% remaining (% remaining intralipid 20% iso)iso) iso) iso) iso) 2 100 95 95 92 91.7 3 100 93 92 70 69.8 4 100 94 9255 55.3 5 100 96 95 60 58.9

Intralipid emulsions with the indicated amount of isoflurane lookedhomogenous and uniform. Moreover, intralipid reduced the volatility ofisoflurane, as compared with Example 6.

One of skill in the art will realize that emulsions of isoflurane may bemade using other lipids, including other emulsion preparations, such as10% (w/v) Intralipid, using variations of the methods described herein.Other commercially available lipid compositions that may be useful forthe production of the volatile anesthetic compositions of the presentinvention include, but are not limited to, Liposyn® (B. Braun) andNutrilipid® (B. Braun). One of skill in the art will also realize thatemulsions of desflurane, sevoflurane, isoflurane, enflurane,methoxyflurane and halothane may be produced using variations of themethods described herein.

Example 9

Preparation of Emulsified Isoflurane (v/v) in Intralipid and NMP

Pure isoflurane USP (Forane) liquid is mixed with NMP (Sigma-Aldrich) inthe indicated concentrations; the NMP-Isoflurane solution was added tointralipid 20% or 30% (Baxter). The mixture was vortexed vigorously andsonicated for 30 minutes to prepare homogenous isoflurane-NMP-intralipidemulsion.

20% Intralipid NMP Isoflurane Appearance of (%) (%) (%) emulsions 1 7515 10 Homogenous 2 80 10 10 Homogenous

0 h 0.25 h 1 h 16 h 24 h (% re- (% re- (% re- (% re- (% re- Isofluranemaining maining maining maining maining Vehicle (%) iso) iso) iso) iso)iso) 20% 5 100 98 94 88 85 intralipid + 15% NMP 20% 10 100 98 97 93 89intralipid + 15% NMP

Intralipid emulsions with the indicated amount of isoflurane in thepresence of NMP looked homogenous and uniform. In the presence of NMP,intralipid was able to hold more isoflurane than in the absence of NMP,as compared with Example 7. In addition, the combination of intralipidand NMP reduced the volatility of isoflurane, as compared with Example6.

One of skill in the art will realize that emulsions of isoflurane may bemade using other lipids, including other emulsion preparations, such as10% (w/v) intralipid, using variations of the methods described herein.Other commercially available lipid compositions that may be useful forthe production of the volatile anesthetic compositions of the presentinvention include, but are not limited to, Liposyn® (B. Braun) andNutrilipid® (B. Braun). One of skill in the art will also realize thatemulsions of desflurane, sevoflurane, isoflurane, enflurane,methoxyflurane and halothane may be produced using variations of themethods described herein.

Example 10

Preparation of Polysorbate 80 (Tween 80)-Based Emulsified Isoflurane

Isoflurane was added to Tween 80 (3% v/v) for a total volume of 10 ml.The mixture was vortexed vigorously and sonicated for 30 minutes toprepare homogenous isoflurane emulsion. In some cases, 1,2-dimyristoyl-sn-glycero-3-phophocholine (DMPC) was included in theformulation. First, DMPC (0.3% or 0.6%) was dissolved in Tween 80 (3%v/v), then isoflurane was added to the Tween-DMPC mixture, which wasfollowed by 30 minutes of sonication.

3% Tween 80 DMPC Isoflurane Appearance of (%) (%) (%) emulsions 1 95 — 5Homogenous 2 93 0.3 7 Homogenous 3 93 0.6 7 Homogenous

0 h 0.25 h 1 h 16 h 24 h (% re- (% re- (% re- (%re- (% re- Isofluranemaining maining maining maining maining Vehicle (%) iso) iso) iso) iso)iso) 3% Tween 7 100 97 95 91 85 3% Tween + 7 100 98 96 94 89 0.3% DMPC3% Tween + 7 100 100 100 99 94 0.6% DMPC

Tween 80-based emulsions appeared homogenous. When DMPC was added, thesame amount of Tween 80 was able to hold more isoflurane than withoutDMPC. Moreover, the combination of isoflurane with Tween 80 or Tween 80DMPC reduced the volatility of isoflurane, as compared with Example 6.

Example 11

Preparation of Isoflurane Solution (v/v) with Propylene Glycol

Pure isoflurane USP (Forane) liquid was mixed with Propylene Glycol(Sigma-Aldrich) at the indicated concentrations; the mixture wasvortexed vigorously to prepare homogenous isoflurane-Propylene Glycolsolution.

Propylene Glycol Saline Isoflurane Appearance of (%) (%) (%) solutions 190 — 10 Clear 2 70 — 30 Clear 3 72 20 8 Clear

Isoflurane 0 h 0.25 h 1 h 16 h 24 h concentration in (% remaining (%remaining (% remaining (% remaining (% remaining Propylene Glycol iso)iso) iso) iso) iso) 10 100 89 86 44 23 30 100 94 90 53 35

Eight percent, 10% and 30% of isoflurane was mixed with propyleneglycol, and the resulting solutions appeared clear. Moreover, propyleneglycol reduced the volatility of isoflurane, as compared with Example 6.

Example 12

Preparation of Cremophor EL-Based Emulsified Isoflurane

Isoflurane was added to an aqueous solution of Cremophor EL (10% v/v)for a total volume of 10 ml. The mixture was vortexed vigorously andsonicated for 30 minutes to prepare homogenous isoflurane emulsion.

10% Cremophor EL Isoflurane Appearance of (%) (%) the emulsion 1 95 5Milky 2 90 10 Milky

0 h 0.25 h 1 h 16 h 24 h Isoflurane (% re- (% re- (% re- (% re- (% re-Con- maining maining maining maining maining Vehicle centration iso)iso) iso) iso) iso) 10% 5 100 90 85 68 54 Cremophor 10% 10 100 91 87 7360 Cremophor

Cremophor EL-based emulsions with the indicated amount of isofluraneappeared milky. Moreover, the Cremophor EL-based emulsions reduced thevolatility of isoflurane, as compared with Example 6.

Example 13

Preparation of Isoflurane Solution (v/v) with Dimethyl Sulfoxide (DMSO)

Pure isoflurane USP (Forane) liquid was mixed with DMSO (BDH) at theindicated concentrations. The mixture was vortexed vigorously to preparehomogenous isoflurane-DMSO solution. The isoflurane solutions containingDMSO appeared clear.

DMSO Saline Isoflurane Appearance of (%) (%) (%) solutions 1 90 — 10Clear 2 50 — 50 Clear 3 72 20 8 Clear

Example 14

Preparation of Isoflurane Solution (v/v) in Perfluorooctyl Bromide

Pure isoflurane USP (Forane) liquid was mixed with PerfluorooctylBromide (Acros Organics) at the indicated concentrations. The mixturewas vortexed vigorously to prepare homogenous isoflurane-PerfluorooctylBromide solution. The isoflurane solutions containing PerfluorooctylBromide appeared clear.

Perfluorooctyl Bromide Isoflurane Appearance of (%) (%) solutions 1 9010 Clear 2 80 20 Clear

Example 15

Preparation of Isoflurane Solution (v/v) in PEG 400

Isoflurane (2 mL) was mixed with PEG-400 (2 mL) in a vial and contentswere shaken resulting in a clear solution. The volatility of theresulting solution was compared to the volatility of pure isofluraneusing Exetech Heavy Duty Differential Pressure Manometer Model 407910.At least a 3 fold reduction of vapor pressure was observed when heatedto about 39° C.

Example 16

Preparation of Isoflurane Solution (v/v) in PEG 300

Isoflurane (2 mL) was mixed with PEG-300 (2 mL) in a vial and contentswere shaken resulting in a clear solution. The volatility of theresulting solution was compared to the volatility of pure isofluraneusing Exetech Heavy Duty Differential Pressure Manometer Model 407910.At least a 3 fold reduction of vapor pressure was observed when heatedto about 39° C.

Example 17

Preparation of Isoflurane Solution (v/v) in Diethylene Glycol MonoethylEther

Isoflurane (2 mL) was mixed with diethylene glycol monoethyl ether (2mL) in a vial and contents were shaken resulting in a clear solution.The volatility of the resulting solution was compared to the volatilityof pure isoflurane using Exetech Heavy Duty Differential PressureManometer Model 407910. At least a 3 fold reduction of vapor pressurewas observed when heated to about 39° C.

The disclosures of each and every patent, patent application, andpublication cited herein are hereby incorporated herein by reference intheir entirety.

All of the compositions and methods disclosed and claimed herein may bemade and executed without undue experimentation in light of the presentdisclosure. While the compositions and methods of this invention havebeen described in terms of preferred embodiments, it will be apparent tothose of skill in the art that variations may be applied to thecompositions and methods and in the steps or in the sequence of steps ofthe method described herein without departing from the concept, spiritand scope of the invention. More specifically, it will be apparent thatcertain agents which are both chemically and physiologically related maybe substituted for the agents described herein while the same or similarresults would be achieved. All such similar substitutes andmodifications apparent to those skilled in the art are deemed to bewithin the spirit, scope and concept of the invention as defined by theappended claims.

While this invention has been disclosed with reference to specificembodiments, it is apparent that other embodiments and variations ofthis invention may be devised by others skilled in the art withoutdeparting from the true spirit and scope of the invention. The appendedclaims are intended to be construed to include all such embodiments andequivalent variations.

What is claimed is:
 1. A method of treating a dermatological disorder ordisease in a subject in need thereof, wherein said method comprisesadministering to said subject a pharmaceutically acceptable composition,wherein said composition comprises a pharmaceutically acceptableexcipient and at least one component selected from the group consistingof: (a) a metered amount of a volatile anesthetic dissolved in asolution in an amount effective to treat said dermatological disorder ordisease, wherein said solution further comprises at least one extractivesolvent in an amount effective to reduce volatility of said volatileanesthetic, wherein said solution is a component of an emulsion; (b) ametered amount of a liposome suspension comprising a volatile anestheticin an amount effective to treat said dermatological disorder or disease;(c) a metered amount of a volatile anesthetic dissolved in a solution inan amount effective to treat said dermatological disorder or disease,wherein said solution further comprises at least one extractive solventin an amount effective to reduce volatility of said volatile anesthetic,wherein said composition further comprises a solubilizing agent; (d) ametered amount of a micro-droplet suspension, wherein said micro-dropletsuspension comprises a sphere of a volatile anesthetic in an amounteffective to treat said dermatological disorder or disease, wherein saidsphere is surrounded by a stabilizing layer of a phospholipid; and anycombinations thereof, wherein said volatile anesthetic is selected fromthe group consisting of isoflurane, halothane, enflurane, sevoflurane,desflurane, methoxyflurane, and any mixtures thereof; wherein saiddermatological disorder or disease is selected from the group consistingof itching, dry skin, sunburn, scab healing, scar growth, and anycombinations thereof, whereby said dermatological disorder or disease insaid subject is treated.
 2. The method of claim 1, wherein said at leastone extractive solvent is selected from the group consisting of dimethylsulfoxide (DMSO), N-methyl-2-pyrrolidone (NMP), dimethylformamide,dimethylacetamide, dimethylisosorbide, ethanol, propanol, PEG-400,PEG-300, diethylene glycol monoethyl ether, isopropanol, and anycombinations thereof.
 3. The method of claim 1, wherein saidadministering is performed by a route selected from the group consistingof topical, transdermal, mucosal, rectal, vaginal, and any combinationsthereof.